Advanced Biopharmaceutics

Some common definition:

Pharmaceutics: study of dosage form design.
Biopharmaceutics: Branch of pharmaceutics (pharmaceutical sciences) dealing with the
biological aspects of Pharmaceutical dosage form (drug product).

Physiological
Physiological activity of
properties of drug and
drug and drug products.
drug products

Biopharmaceutics

Bioavailability: Indicate A measurement of the rate and extent (amount) of the therapeutically
active drug that reaches the systemic circulation and is available site of action.
Drug elimination: Drug elimination refers to the removal of drug from the body by all route of
elimination. drug elimination may be divided into two major components.
• Excretion
• Biotransformation
Relationship between pharmacokinetics and pharmacodynamics.

Drug in Drug Dissolution Drug in GI Absorption Drug in

product Fluid Blood

Pharmacokinetics Elimination Drug in

Tissue

Drug executed/
Metabolized

Pharmacodynamics
One compartment open Model –
Intravenous Bolus Administration
The one compartment open model offers the simplest way to describe the process of drug
distribution & elimination in the body. This model assumes that the drug can enter or leave the
body (i.e. – the model is open), & the body acts like a single, uniform compartment. The simplest
kinetic model that describes drug disposition in the body is to consider that the drug is injected
all at once into a box, or compartment, & that the drug distributes instantaneously &
homogenously throughout the can compartment.

Elimination

Distribution
One compartment model

Compartment Analysis
Compartmental Model in pharmacokinetics:
A pharmacokinetic model is divided as complex biological system which describes the:
• Movement of drugs
• Absorption of drugs
• Distribution of drugs
• Elimination of drugs from one or more compartment

Classification –
Pharmacokinetic
Model

Compartmental Physiologic Model

Model (Tissue sampling
(Plasma Sampling) required for animals)

Mammilary model Catenary Model

(Sattelite) (Train)

One compartment Two compartment Three Compartment

open Model model Model
Purpose of pharmacokinetic model:
• To determine plasm, tissue, urine drug level with any drug dose.
• To determine optimum dosage regimen for each patient.
• To determine the possible accumulation of drug or metabolites.
• To correlate the drug concentration with pharmacological /toxicological activity.
• To indicate the physiological effect on drug absorption, distribution and elimination.
• To explain drug interaction
• To evaluate bioequivalence of the products.
Importance of compartmental analysis:
▪ To determine the distribution pattern of drug in our body.
▪ To determine the concentration of drug in different compartment
▪ To determine the steady state of drug
▪ To determine various pharmacokinetic parameters –
𝐶𝑙
• Volume of distribution (𝑉0 = 𝑡⁄𝐾 )
• Elimination half-life (𝑡1 = 0.693⁄𝐾 )
2
𝐶𝑙 𝑇
• Elimination rate constant (𝐾 = ⁄𝑉 )
𝐷
• Total body clearance (𝐶𝑙 𝑇 = 𝐾𝑉𝐷 )
▪ To determine bioavailability of drug.
▪ To determine renal excretion rate constant.
▪ Indicates the change of drug from drug administration to elimination from the body.
▪ Gives the idea of protein binding of the drug.
Limitations of Compartment analysis –
▪ Compartment is not a real physiologic or anatomic region.
▪ It cannot predict the realistic tissue drug concentration.
▪ On the basis of routes of administration some drugs may follow one or two
compartments.
e, g., –
Theophylline & Lidocaine = in oral route – Follow one compartment.
Aminophylline = in IV route – Follow 2 compartment.
▪ Here person to person variation is high.
e.g. – fatty person – drugs may follow 3 compartments.
Why compartments are called kinetically distinguishable pool?
Ans – When a drug enters into a pool; it achieves a particular absorption & elimination route.
But due to the intrinsic property (enzymatic) of the pool, it holds up some drugs. So, the route of
drug absorption & elimination will not be same.
 For IV
For Oral
Q. Kb
Q. G 1 Q. Cb 2
Ka Kb

K2
Let,
Drug concentration absorbed = Ca
Drug Concentration elimination = Cb
Quantity of blood flow = Q
Amount of drug entered = Q. Ca
Amount of drug eliminated = Q. Cb
As drug concentration, differs, so the rate also differs. So, the amount of drug held up by the pool
is again excreted by another rate K2.
So, we can distinguish pool as two different compartments.
What is a compartment from pharmacokinetic point?
Ans: There are 3 types of pharmacokinetic models. They are –
➢ Compartment model – Describes the pharmacokinetics of drug disposition by grouping
body tissues that are kinetically indistinguishable & describe the transfer of drug between
body tissues in terms of rate constants.
➢ Non compartment model – Describes the pharmacokinetics of drug disposition using
time & concentration averaged parameters.
➢ Physiological model – Attempt to describe drug disposition in terms of realistic
physiological parameters such as local blood flow & tissue – partition co – efficient.
From pharmacokinetics viewpoint, a compartment is a kinetically distinguished pool. If we
distinguish two areas kinetically, then they will be compartments.
The body can be represented as a series or system of compartments, that communicate reversibly
with each other. A compartment is not a real physiological or anatomical region but it is
considered as a tissue or group of tissues that have –
o Similar blood flow
o Similar drug affinity
o Uniform drug distribution (absorption & elimination)
K1 K2 K3 K4
1 2

If 𝐾1 ≠ 𝐾3 & 𝐾2 ≠ 𝐾4 then it will be different compartment.

Compartment – A compartment is usually defined as a kinetically distinguishable pool in terms
of drug concentration – time profile.
Importance –
✓ A compartment is not a real physiologic/ anatomic region.
✓ Within each compartment the drug is considered to be uniformly distributed.
✓ Rate constants are used to represent the overall rate processes of drug enters into & exit
from the compartment.
✓ The amount of drug in the body is the sum of the drug present in the central compartment
as well as in the tissue compartment. (DB = Dp + Dt).
Classification of compartmental model –
❖ Depending on the rate of drug distribution –
➢ Central Compartment –
Central compartment represent of compartment into which drug distributes rapidly
& uniformly. Example – tissues.
➢ Peripheral Compartment –
The peripheral compartment represents a correspondent into which drug
equilibrates more slowly. Example – tissues.
It is also known as “tissue compartment”.
K12
Central Peripheral
K21

The distribution of drugs between the two compartments follows the 1st order rate process.
❖ Depending on the arrangement of compartment –
➢ Mammillary model – Mammillary model consists of one/more peripheral
compartments connected to the central compartment (like – satellite). Most
common model used pharmacokinetics.
3

4 Central 2

1
➢ Catenary model – The category model consists of compartments joined to each
other like a train.

1 2 3
 ❖ Depending on the number of compartments –
➢ One compartment
➢ Multi Compartment
Multi
compertment

Two Three
compertment compertment
model model

Closed Open

Non -
Equivalent
Equivalent

What are the advantages of mammillary model over catenary model system?
Ans – Because –
✓ It is the strongly connected system in which one can estimate the amount of drug
in any compartment.
✓ Very much close to physiological process.
✓ In case of IV products, drug enters into the body & distributed as a single
compartment, which is similar as mammillary model.
Equivalent compartment – Equivalent compartment are those comportments in which the given
drug in one compartment is equally distributed into the compartment involved.
Non – equivalent compartment – Given drug in one compartment is not equally distributed into
the compartment.
Parameters in which the equivalent & non – equivalent compartment systems are involved –
o Constituents in each compartment
o Volume of fluid compartment
o Plasma protein concentration.
o Ionization capacity of solution.
One compartment open model –
It is the model where the drug is distributed in one compartment & eliminated from here.

Volume Vd Dn
KCl
Ka DB
D0
ab Cp elimination
Dm

D0 = Drug absorbed
Ka = absorption rate
Vd = Apparent volume of distribution
Cp = Concentration of drug
KCl = Elimination rate constant
Dn = Amount of drug excreted in urine
Dm = Amount of drub metabolized
Characteristics –
➢ In this model, the body is assumed to behave as a single compartment. It means as if
there were no barriers to movement of drug within the total body space.
➢ In this model, drug distribution is unidirectional & instantaneous.
➢ It implies that changes in the plasma levels of a drug will result in proportional changes
in tissue drug level.
➢ The drug in the body (DB) can’t be measured directly, but accessible body fluids (e.g.
blood) can be sampled to determine drug concentration (CP).
➢ One compartment model has two parameters –
o Apparent volume of distribution (Vd)
o Elimination rate constant (k)
Vd governs the plasma concentration of drug (CP) after a certain time & a given dose. K
governs the rate at a time.
Limitation –
o It does not assume that drug concentration in all tissue level are same.
o Drug in the body cannot determine directly.
How can you measure the elimination rate constant (K) for a drug? When the drug acts as
a single compartment?
Or, Determine the amount of drug (D0) at any time.
The rate of elimination is 1st order rate process. As we know, the elimination rate constant is the
sum of metabolism rate constant & excretion rate constant.
K = Km + Kc
K = elimination rate constant
Km = Metabolism rate constant
Kc = Excretion rate constant.
If the rate of absorption & rate of elimination is same, the body acts a single compartment. Let a
drug is given in IV route.

K
IV Cp, Vd, DB

So, the elimination rate at time “t” can be expressed as,

𝑑𝐷𝐵
= −𝐾𝐷𝐵
𝑑𝑡
𝐷 𝑑𝐷𝐵 𝑡
Or, ∫𝐷′𝐵 = −𝐾 ∫0 𝑑𝑡 D’B = amount of drug in body, when t = 0.
𝐵 𝐷𝐵

𝐷𝐵
Or, ln = −𝐾 (𝑡 − 0)
𝐷′𝐵
DB = amount of drug in body, when time = t
𝐷𝐵
Or, ln = −𝐾𝑡
𝐷′𝐵

𝐷𝐵 𝑘𝑡
Or. log = −
𝐷′𝐵 2.303

𝐾𝑡
Or, log 𝐷𝐵 = log 𝐷′𝐵 − -------- (1)
2.303

∴ 𝐷𝐵 = 𝐷′𝐵 𝑒 −𝑘𝑡 ----- (2)

We know,
𝐷𝐵
𝑉𝐷 =
𝐶𝑃

∴ 𝐷𝐵 = 𝑉𝑑 𝐶𝑃 ----- (3)

From equation – 3,
𝐶𝑃 𝑉𝑑 = 𝐶′𝑃 𝑉𝑑 𝑒 −𝐾𝑡
𝐶𝑃 = 𝐶′𝑃 𝑒 −𝐾𝑡 ------ (4)

This is the equation of a drug in plasma concentration when body acts a single compartment.
𝐾
∴ log 𝐶𝑃 = log 𝐶′𝑃 −
2.303

Graphical representation –
From the equation we get,
𝐾
log 𝐷𝐵 = log 𝐷′𝐵 −
2.303
𝐾
Or, log 𝐷𝐵 = − + log 𝐷′𝐵
2.303
→ 𝑙𝑜𝑔𝐷𝐵

𝑡 →

From graph,
−𝐾
Slope =
2.303

∴ 𝐾 = −𝑠𝑙𝑜𝑝𝑒 × 2.303
Apparent volume of distribution –
The apparent volume in which the drug is dissolved, is called apparent volume of distribution.
Because the value of VD does not have a true physiologic meaning in terms of an anatomic
space, the term apparent volume of distribution is used.
VD is a useful parameter that relates plasma concentration (CP) to the amount of drug in the body
(DB).
𝐷𝐵
𝑉𝐷 =
𝐶𝑃

Significance –
• We can measure the amount of drug in the body with VD.
𝐷𝐵 = 𝑉𝐷 𝐶𝑃
 • We can get idea about the distribution pattern of a drug. If VD is large, the drug is
distributed in extra – vascular tissues. Conversely, for polar drugs with low lipid
solubility, VD is generally small.
• We can determine the nature of drug whether they are acidic or basic. VD is less, drug is
acidic (e.g. – penicillin); VD is high, drug is basic (e.g. – metronidazole).
• We know,
𝑑𝑜𝑠𝑒 1
𝑉𝐷 = ; 𝑠𝑜 𝑎𝑡 𝑐𝑜𝑛𝑡𝑎𝑛𝑡 𝑑𝑜𝑠𝑒, 𝑉𝐷 ∝
𝐶𝑃 𝐶′𝑃
• VD can be expressed as % of body weight. Let, A patient has VD 3900 ml & body weight
is 70 kg.
3.5 𝑘𝑔
𝑉𝐷 = × 100 = 9% 𝑜𝑓 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 [3500 ml = 3500 g = 3.5 kg]
70 𝑘𝑔
• If VD ≥ 100% of body weight, that we can say that drug is concentrated in certain tissue
compartment (outside the central compartment).
How can you calculate the volume of distribution (VD) of a drug from one – compartment
open model?
We can calculate the volume of distribution (VD) by the following two methods –
o Model dependent method
o Model independent method.
Model dependent method –
In a one compartment model (IV administration) the VD is calculated with the following
equation,
𝐷𝑜𝑠𝑒 𝐷′𝐵
𝑉𝐷 = = 100
𝐶′𝑃 𝐶′𝑃

For, IV administration, C’P

Dose = initial drug dose – D’B
CP →

C’P = initial plasma concentration at time, t = 0.

Graph for calculation of C’P
0 100
Here, Intercept = C’P; t→

Model independent method –

Let a drug is given intravenously,
K
IV DB, VD, CP

A rate expression for 1st order (as elimination rate constant is 1st order) →
 𝑑𝐷𝐵
= −𝑘. 𝐷𝐵
𝑑𝑡
Or, 𝑑𝐷𝐵 = −𝑘. 𝐷𝐵 . 𝑑𝑡
𝐷𝐵
Or, 𝑑𝐷𝐵 = −𝑘. 𝑉𝐷 . 𝐶𝑃 . 𝑑𝑡 [∴ 𝑉𝐷 = ]
𝐶𝑃

As both k & VD are constants, previous equation may be integrated as follows;

∝ ∝
∫0 𝑑𝐷𝐵 = −𝑘𝑉𝐷 ∫0 𝐶𝑃 . 𝑑𝑡

This equation shows that a small change in time (dt) results in a small change in the amount of
drug in the body DB.
∝
The integral ∫0 𝐶𝑃 . 𝑑𝑡 represents the which is the summation of the area under the curve from t
= 0 to t = α, thus VD may also be calculated from the dose, elimination rate constant & area
under curve from t = 0 to t = α.
Or, − 𝐷′ 𝐵 = −𝑘 𝑉𝐷 [ 𝐴𝑈𝐶]∝0
𝐷′𝐵 = 𝑘𝑉𝐷 [𝐴𝑈𝐶]∝0
𝐷𝑜𝑠𝑒
∴ 𝑉𝐷 =
𝑘 [𝐴𝑈𝐶]∝
0

How can you measure elimination rate constant from urinary excretion data?
The elimination rate constant k may be calculated from urinary excretion data. In this
calculation, the excretion rate of the drug is assumed to be first order. The term is the renal
excretion rate constant & Dn is the amount of drug excreted in the urine.
𝑑𝐷𝑛
= 𝐾𝑐 𝐷𝐵
𝑑𝑡
𝑑𝐷𝑛
Or, = 𝑘𝑐 . (𝐷′ 𝐵 𝑒 −𝑘𝑡 )[ℎ𝑒𝑟𝑒, 𝐷𝐵 = 𝐷′ 𝐵 . 𝑒 − 𝑘𝑡 ]
𝑑𝑡
𝑑𝐷𝑛
Or, ln = ln[𝐾𝑐 𝐷′ 𝐵 𝑒 − 𝑘𝑡 ]
𝑑𝑡
𝑑 𝐷𝑛
Or, ln = ln 𝐾𝑐 𝐷𝐵 − 𝑘𝑡 [∴ ln 𝑒 −𝑘𝑡 = −𝑘𝑡]
𝑑𝑡
𝑑𝐷𝑛
Or, ln = −𝑘𝑡 + ln 𝐾𝐶 . 𝐷′𝐵
𝑑𝑡
𝑑𝐷𝑛 − 𝑘𝑡
Or, log = + log 𝐾𝐶 𝐷′𝐵
𝑑𝑡 2.303

Graphical representation – log 𝐾𝐶 𝐷′𝐵

−𝑘
𝑠𝑙𝑜𝑝𝑒 =
𝑑𝐷𝑛 2.303
log
𝑑𝑡

Time →
From graph,
−𝑘
𝑠𝑙𝑜𝑝𝑒 =
2.303
∴ 𝑘 = −𝑠𝑙𝑜𝑝𝑒 × 2.303
0.607
∴ 𝑠𝑜, ℎ𝑎𝑙𝑓 𝑙𝑖𝑓𝑒, 𝑡1 =
2 𝑘

Intercept = log 𝐾𝑐 . 𝐷′𝐵

𝑎𝑛𝑡𝑖 log(𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡) 𝐴𝑛𝑡𝑖 log(𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡)
∴ 𝐾𝑐 = =
𝐷𝐵 𝑑𝑜𝑠𝑒

Determination of non – renal elimination rate constant (Knr) –

We know that,
K = Km + Kc
Or, K – Ke = Knr
Here,
K = elimination rate constant
Km = metabolism rate constant
Ke = excretion rate constant
For most drugs, major route of elimination for most drugs are renal excretion & metabolism
(biotransformation) Knr is approximately equal to Km.
Knr = Km
So, K – Ke = Knr
Precautions for measurements –
➢ Drug should not be highly metabolized.
➢ Metabolite should not have structures similarity, as interference can be arised.
➢ Patient should be advised to collect complete amount of urine.
➢ Alternate method of “k” by urinary excretion data.
Sigma – minus method –
The amount of unchanged drug in urine can be expressed as,
𝐾𝑒 𝐷0
𝐷𝑛

𝐷𝑛 = (1 − 𝑒 − 𝑘𝑡 ) -------- (1)
𝐾

Dn = cumulative amount of drug.

The amount of unchanged drug that is ultimately excreted in the urine – t→
Fig – Cumulative urinary
excretion of drug vs time
 𝐾𝑒 𝐷0
𝐷𝑢∝ = [ as at time, t = ∝ ∴ 𝑒 − 𝑘𝑡 ≅ 0]
𝐾

From – 1,
𝐷𝑢 = 𝐷𝑢∝ (1 − 𝑒 − 𝑘𝑡 )
Or, 𝐷𝑛 = 𝐷𝑛∝ − 𝐷𝑢∝ 𝑒 − 𝑘𝑡
Or,𝐷𝑛∝ − 𝐷𝑛 = 𝐷𝑢∝ 𝑒 − 𝑘𝑡
𝑘𝑡
Or, log(𝐷𝑢∝ − 𝐷𝑛 ) = log 𝐷𝑢∝ −
2.303

Drug clearance in the one compartment model –

The body is considered as a system of organs perfused by plasma & body fluids. Drug clearance
refers to the volume of plasma fluid that is cleared of drug per unit time. Clearance may also be
considered as the fraction of drug removed per unit time.
The rate of drug elimination may be expressed in several ways which describes the same process
but with different levels of insight & application in pharmacokinetic.
Drug elimination expressed as volume per unit time –
Clearance is a concept the express “the rate of drug removal” in terms of volume of drug solution
removed per unit time.
Clearance for a first order process is constant because clearance is expressed in volume per unit
time rather than drug amount per unit time.
Here,
𝑑𝐷𝐵
= −𝑘 𝐷𝐵 [ elimination rate constant is a first order process.]
𝑑𝑡
𝑑𝐷𝐵
Or, = −𝑘. 𝐷𝐵
𝑑𝑡
𝑑𝐷𝐵 𝐷𝑜𝑠𝑒
Or, = −𝑘. 𝐶𝑃 𝑉𝑑 [∴ 𝑉𝑑 = ]
𝑑𝑡 𝐶𝑃

𝐷
𝑑 𝐵⁄𝑑𝑡 − 𝑘.𝐶𝑃 .𝑉𝑑
Or, = [𝑑𝑖𝑣𝑖𝑑𝑖𝑛𝑔 𝑏𝑦 𝐶𝑃 𝑖𝑛 𝑏𝑜𝑡ℎ 𝑠𝑖𝑑𝑒𝑠]
𝐶𝑃 𝐶𝑃

𝐷
𝑑 𝐵⁄𝑑𝑡
Or, = −𝑘. 𝑉𝑑
𝐶𝑃

𝐷
𝑑 𝐵⁄𝑑𝑡
Or, = −𝐶𝑙 ---- (1) [k. Vd = Cl]
𝐶𝑃

Here,
 𝑑𝐷𝐵
= Rate of drug elimination
𝑑𝑡

CP = Plasma concentration of drug

K = elimination rate constant
Cl = Total body clearance
Vd = Apparent volume of distribution
From equation – 1, elimination rate constant & apparent volume of distribution is constant, so
the clearance may also be referred as a constant. The negative sign refers as the removal of dug
from the body.
Clearance & volume of distribution ratio – (Cl/Vd)
Let us consider that 100 mg of drug is dissolved in 10 ml of fluid & 10 mg of drug is removed in
the first minute. The drug elimination process could be described as,
➢ Number of mg of drug eliminated per minute (mg/min)
➢ Number of ml of fluid cleared of per minute
➢ Fraction of drug eliminated per minute.
The fraction Cl/Vd is dependent on both the volume of distribution & the rate of drug clearance
from the body. If the drug concentration is CP, the rate of drug elimination (dCP/dt) is –
𝑑𝐶𝑃 𝐶𝑙
= − ( ) × 𝐶𝑃
𝑑𝑡 𝑉𝑑

For a first order process,

𝑑𝐶𝑃
> −𝑘 𝐶𝑃 = 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛.
𝑑𝑡

Equating the two expression yields –

𝐶𝑙
𝑘 𝐶𝑃 = × 𝐶𝑃
𝑉𝑑

𝐶𝑙
𝑘=
𝑉𝑑

Thus, a final order rate constant is the fractional constant Cl/Vd.

Calculation of elimination rate constant (k) or half life (t ½) when two plasma samples &
their time of collection is known.
The most accurate kinetic method to determine the volume of distribution is to give the drug by a
single IV bolus dose. At IV dose avoids many variables such as delayed, irregular or incomplete
absorption compared to other routes of administration.
For IV single dose,
ln 𝐶𝑃 = ln 𝐶′𝑃 − 𝑘𝑡 ------ (1)
For equation – 1 may be modified to calculate the elimination rate constant or half-life of a drug
in a patient when two plasma samples & their time collection are known. If the plasma sample is
taken at t1 instead of at zero & corresponds to plasma drug concentration, the C2 is the
concentration at time t2 & t is sCl to (t2 – t1).
𝐶2 = 𝐶1 𝑒 − 𝑘 (𝑡2 − 𝑡1 )
Or, ln 𝐶2 = ln 𝐶1 − 𝑘 (𝑡2 − 𝑡1 )
Rearranging the equation,
ln 𝐶2 − ln 𝐶1 = −𝑘 (𝑡2 − 𝑡1 )
ln 𝐶1 − ln 𝐶2 0.693 (𝑡2 − 𝑡1 )
∴𝑘= ; 𝑡1 =
𝑡2 − 𝑡1 2 ln 𝐶1 − ln 𝐶2
When,
t1 = time of first sample collection
C1 = Plasma drug concentration at t1
t2 = time of second sample collection
C2 = Plasma drug concentration at t2
If the drug in the body is in a declining phase, this equation may be used to determine the half-
life of the drug in the patient by taking 2 plasma samples for apart & recording the times of
sampling.
 Two compartment open model

Definition – Two compartment open model is the model in which drug is distributed into two
compartments & then is eliminated from these compartments (mainly from central
compartments).
1 K12 2
Central Peripheral
K21
K10 K20

Properties –
▪ The whole system is open.
▪ Distribution & elimination is 1st order rate process.
▪ Elimination mainly occurs from central compartment.
▪ Equilibrium condition depends on the rate of equilibration.
▪ Equilibrium may or may not be achieved.
▪ The time at which peak tissue concentration is attained indicates the equilibrium time
between two compartments.
▪ The falling of tissue & plasma concentration is parallel.
▪ Drug is distributed into 2 compartments.
Distribution pattern (components) –
In two compartmental model, drug is distributed into two compartments –
▪ Central compartment – Drug is distributed rapidly & uniformly in the central
compartment. Example – Blood, extra cellular fluid, Highly perfused tissues (kidney,
liver.)
▪ Peripheral compartment – Drug is distributed & equilibrated more slowly. Example –
tissues.
Example of drugs – Aspirin, Penicillin G, Theophylline, Amphetamine, Thiopental.
Types –
➢ Model – A: It is the most often used model & described the plasma level time curve.
1 K12
Central Peripheral
K21
K10
 ➢ Model – B: 1 K12 2

Central Peripheral
K21
K20

➢ Model – C:
1 2

Central Peripheral

K10 K20

Maximum two compartment models assume that elimination occurs from the central
compartment.
Drug elimination occurs from central compartment because the major sites of drug elimination
(hepatic metabolism, renal excretion) occur in organs such as kidney, liver, heart which are
highly perfused with blood.
The plasma level time curve can be divided into two parts –
o Distribution phase (a)
o Elimination phase (b)

a = distribution phase
Plasma Level →

b = elimination phase
b

t →

Distribution phase – It represents the rapid decline of drug from the central compartment to the
tissue compartment. The fraction of drug in the tissue compartment increases to achieve the
equilibrium & plasma level decreases slowly & gives a non-linear curve.
Elimination phase – In this phase, drug concentration declines slowly then distribution phase.
At certain stage, concertation of drug in the two phases become same & elimination phase starts.
After equilibrium, concentration of drug in both plasma & tissue compartments decline more
slowly & the curve shows a linear 1st order elimination rate process.
After an intravenous dose, initially (at time, t = 0) these is no drug in the tissue compartment
because drug is distributed to the central compartment at first & equilibrium into it. Then drug is
rapidly transferred from the central compartment to the tissue compartment. For this, tissue drug
concentration becomes peak & then declines slowly.

Drug concentration →
plasma

tissue
time →

Relationship between tissue &

plasma drug concentration

But in case of central compartment, drug concentration declines more rapidly because –
✓ Elimination of drug
✓ Transfer of drug from the central compartment at a time.
Time course for concentration in blood, tissue & elimination compartment
➢ Curve B – Concentration of drug is decreasing with time in blood (B)
➢ Curve T – Concentration of drug is increasing with time in tissue (T) then decreases.
➢ Curve C – Elimination of drug is increased with tissue.

B
C
T
Drug concentration →

time →
Basic questions about compartmental analysis

1. What does the word “open” mean in the one compartment open model?
Ans: The term open indicates that the input (availability) and output
(elimination) are unidirectional and that the drug can be eliminated from the body.

2. How much time does an intravenously administered drug take to complete a

complete circulation?
Ans: With IV administration, onset is usually within 1 minute, with a peak at 2 to 6
minutes and recovery within 30 to 60 minutes.

3. What is meant by elimination half-life?

Ans: The definition of elimination half-life is the length of time required for the
concentration of a particular substance (typically a drug) to decrease to half of its
starting dose in the body.

4. The i.v. bolus dosage is 500mg and the plasma drug concentration is 0.8 mg/ml.
What should be the volume of distribution?

5. Why compartment is kinetically distinguishable pool?

Ans: When a drug enters into a pool; it achieves a particular absorption & elimination
route.
But due to the intrinsic property (enzymatic) of the pool, it holds up some drugs. So,
the route of drug absorption & elimination will not be same.

6. What is pharmacokinetic model?

Ans: A pharmacokinetic model is divided as complex biological system which
describes the:
• Movement of drugs
• Absorption of drugs
• Distribution of drugs
• Elimination of drugs from one or more compartment

7. Central and peripheral compartment

Ans: Central Compartment –Central compartment represent of compartment into
which drug distributes rapidly & uniformly. Example – tissues.
➢ Peripheral Compartment –
The peripheral compartment represents a correspondent into which drug
equilibrates more slowly. Example – tissues.

8. Distribution and elimination phase

vd=DB/cp= 500mg / 0.8mg/ml
Intravenous Infusion – A solution administered into a vein through an infusion set that
includes set that includes a plastic or glass vacuum bottle or bag containing the solution &
tubing connecting the bottle to a catheter or a needle in the patient’s vein.
Loading Dose – A dose of medication, often larger than subsequent doses, administered for
the purpose of establishing a therapeutic level of medication.
Maintenance dose – The amount of medication administered to maintain a desired level of
the medication in blood.
Example of parenteral routes of administration include – Intravenous, Subcutaneous &
intramuscular.
Advantages of giving by IV –
➢ It allows precise control of plasma drug concentration to fit the individual needs of the
patient.
➢ For drugs with narrow therapeutic window (e.g., heparin), IV infusion maintains an
effective constant plasma drug concentration by eliminating wide fluctuations
between the peak (maximum) & through (min) plasma drug concentration.
➢ Some IV infusions (e.g. - antibiotic) may be given with IV fluids that include
electrolyte & nutrients.
➢ The duration of drug therapy may be maintained or terminated.
Steady state level in Intravenous Infusion –
Steady state level – SSL is a level that indicates plasma drug concentration come from peak
point & goes to steady state. It must lie between minimum effective concentration (MEC) &
Maximum Therapeutic concentration (MTC).

At steady state level, no drug was present in the body at zero-time, drug level rises from 0 –
drug concentration & gradually become constant when a platean or steady state drug
concentration is reached.
Here, infusion rate & elimination rate is same.
So, Rate of drug input = Rate of drug output
(Infusion rate) (elimination rate)
One compartment model drug in Intravenous Infusion
The pharmacokinetics of a drug given by constant IV infusion follows a “0” – order input
process in which the drug is infused directly into systemic blood circulation. For most drug
elimination follows the first order process.
The amount of drug at any time = Rate in (0 order) – Rate out (1st order)
𝑑𝐷𝐵
= 𝑅 − 𝐾𝐷𝐵 -------- (1)
𝑑𝑡

Here,
𝐷𝐵 = amount of drug in body
R = Infusion rate
K = Elimination rate
Integration & Substitution of equation 1,
𝑅
𝐷𝐵 = (1 − 𝑒 − 𝑘𝑡 )
𝐾
𝑅
⇒ 𝐶𝑃 . 𝑉𝐷 = (1 − 𝑒 − 𝑘𝑡 )
𝐾

𝑅
⇒ 𝐶𝑃 = (1 − 𝑒 − 𝑘𝑡 )
𝐾𝑉𝐷
At the increasing of time in infusion,
𝑡 = ∝, 𝑠𝑜, 𝑒 − 𝑘𝑡 = 0
𝑅
∴ 𝐶𝑃 =
𝐾𝑉𝐷
From the definition of steady state level,
𝑅 𝑅
𝐶𝑆𝑆 = = (𝐾. 𝑉𝐷 = 𝑐𝑙𝑒𝑎𝑟)
𝐾.𝑉𝐷 𝐶𝑙
Infusion method for calculating patient Elimination Half Life?
The CP – Vs – time relationship that occurs during on IV infusion is used to calculate K.
Here, Plasma concentration of IV dose,
𝑅
𝐶𝑃 = (1 − 𝑒 − 𝑘𝑡 ) ------- (1)
𝐾𝑉𝐷

& often infusion, steady – state level is observed. So, concentration of steady state level,
𝑅
𝐶𝑆𝑆 = -------- (2)
𝐾.𝑉𝐷

From equation 1,
𝐶𝑃 = 𝐶𝑆𝑆 (1 − 𝑒 − 𝑘𝑡 )
𝐶𝑃
Or, = (1 − 𝑒 − 𝑘𝑡 )
𝐶𝑆𝑆

𝐶𝑃
Or, 1 − = ( 𝑒 − 𝑘𝑡 )
𝐶𝑆𝑆

𝐶𝑆𝑆 − 𝐶𝑃
Or, = ( 𝑒 − 𝑘𝑡 )
𝐶𝑆𝑆

Rearranging log on both sides,

𝐶𝑆𝑆 − 𝐶𝑃 − 𝑘𝑡
log =
𝐶𝑆𝑆 2.303
− 2.303 𝐶𝑆𝑆 − 𝐶𝑃
Or, 𝐾 = log
𝑡 𝐶𝑆𝑆

The above equation shows the first order & as we know, we can calculate easily the 𝑡1⁄ from
2
first order rate constant.
0.693
∴ 𝑡1⁄ =
2 𝐾

Loading dose plus IV infusion: One compartment model –

The loading dose, DL, or initial bolus dose of a drug, is used to obtain desired concentrations
as rapidly as possible. The concentration of drug in the body for a one compartment model
often on IV bolus dose is described by,
𝐷𝐿
𝐶1 = 𝐶0 . 𝑒 − 𝑘𝑡 = . 𝑒 − 𝑘𝑡 --------- (1)
𝑉𝐷

& Concentration by infusion at the rate “R” is –

𝑅
𝐶2 = (1 − 𝑒 − 𝑘𝑡 ) --------- (2)
𝑉𝐷 𝐾

So, the total concentration “CP” at “t” hours after the start at infusion is,
C1 + C2; DL = Loading dose
𝐶𝑃 = 𝐶1 + 𝐶2
 𝐷𝐿 𝑅
𝐶𝑃 = . 𝑒 − 𝑘𝑡 + (1 − 𝑒 − 𝑘𝑡 )
𝑉𝐷 𝑉𝐷 𝐾
𝑅 𝐷𝐿 𝑅
𝐶𝑃 = ( . 𝑒 − 𝑘𝑡 + 𝑒 − 𝑘𝑡 ) ------- (3)
𝑉𝐷 𝐾 𝑉𝐷 𝑉𝐷 𝐾

Let, the loading dose (DL) equal the amount of drug in the body at steady state;
𝐷𝐿 = 𝐶𝑆𝑆 . 𝑉𝐷
𝑅 𝑅
Or, 𝐷𝐿 = [ 𝐶𝑆𝑆 = ∴ 𝐶𝑆𝑆 . 𝑉𝐷 = 𝑅⁄𝐾 ]
𝐾 𝑉𝐷 𝐾

Putting the value of DL in equation – 3 we get,

𝑅 𝑅 𝑅
𝐶𝑃 = ( . 𝑒 − 𝑘𝑡 − 𝑒 − 𝑘𝑡 )
𝑉𝐷 𝐾 𝑉𝐷 𝐾 𝑉𝐷 𝐾
𝑅 𝑅
∴ 𝐶𝑃 = ; Same as 𝐶𝑆𝑆 =
𝑉𝐷 𝐾 𝑉𝐷 𝐾

Therefore, if an IV loading dose is given steady state plasma drug concentrations are obtained
immediately & maintained ss – level.

Estimation of Drug clearance & VD from infusion data –

We know, drug clearance,
𝐶𝑙 = 𝑘. 𝑉𝐷

∴ 𝐾 = 𝐶𝑙⁄𝑉
𝐷

From IV infusion,
𝑅
𝐶𝑃 = (1 − 𝑒 − 𝑘𝑡 )
𝑉𝐷 𝐾

𝑅
𝐶𝑃 = (1 − 𝑒 − 𝑘𝑡 )
𝐶𝑙
𝑅 − (𝐶𝑙⁄𝑉 )𝑡
= (1 − 𝑒 𝐷 )
𝐶𝑙
Intravenous infusion of Two – compartment model drugs –
With two – compartment model drugs, IV infusion requires a distribution & equilibration of
the drug before a stable blood level is reached. During a constant IV infusion, drug in the tissue
compartment is in distribution equilibrium with the plasma; thus, constant CSS levels also result
in constant drug concentrations in the tissue; i.e., no net change in the amount of drug in the
tissue occurs at a steady state. Although some clinicians assume that tissue & plasma
concentrations are equal when fully equilibrated, kinetic models predict only that the rates of
drug transfer into & out of the compartments are equal but may differ from plasma
concentrations.
The time needed to reach a steady blood level depends entirely on the distribution half – life of
the drug.
The equation,
𝑅 𝐾−𝑏 𝑎−𝐾
𝐶𝑃 = [1 − ( ) 𝑒 − 𝑎𝑡 − ( ) 𝑒 − 𝑏𝑡 ]
𝑉𝑝 𝐾 𝑎−𝑏 𝑎−𝑏

Here,
a & b = hybrid rate constants
R = rate of infusion
At steady state level, 𝑡 = ∝
𝑅
𝐶𝑆𝑆 =
𝑉𝑝 𝑘

𝑅 = 𝐶𝑆𝑆 𝑉𝑝 𝑘

Apparent volume of Distribution of Steady state – Two compartment Model after

adjusting Loading dose
The volume of distribution at steady state (𝑉𝐷 )ss is the “hypothetical space” in which the drug
is assured to be distributed.
At steady state conditions, the rate of drug entry into the tissue compartment from the central
compartment is equal to the rate of drug exit from the tissue compartment into central
compartment.
These rates of drug transfer are described by the following expression –

𝐷𝑡 𝑘21 = 𝐷𝑃 𝑘12
𝑘12 𝐷𝑃
𝐷𝑡 = ----- (1)
𝑘21

𝐷𝑡 = 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡𝑖𝑠𝑠𝑢𝑒

𝐷𝑃 = 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑝𝑙𝑎𝑠𝑚𝑎
From equation – 1,
𝑘12 𝐶𝑃 𝐷𝑃
𝐷𝑡 = [𝐷𝑃 = 𝐶𝑃 . 𝑉𝑃 ]
𝑘21

Now, the total amount of drug in the body at steady state is equal to the sum of the amount of
drug in tissue & central compartment.
𝐷𝑃 + 𝐷𝑡
(𝑉𝐷 )𝑆𝑆 =
𝐶𝑃
𝑘 𝐶 𝐷
𝐶𝑃 𝐷𝑃 + 12𝑘 𝑃 𝑃
21
=
𝐶𝑃

𝐾12
= 𝑉𝑃 + 𝑉𝑃
𝐾21
❖ A 35 years 65 kg patient is given a drug by IV infusion. According to this,
elimination half – life of drug is 7 hours & VD is 23.1% of body weight. Desired
steady state plasma level is 10 mg/ml.
o Assuming no loading dose, how long after the start of the IV infusion
would take to reach 95% of the Css?
𝑅 Take normal logarithm
𝐶𝑆𝑆 = 95% 𝐶𝑠𝑠 𝑙𝑒𝑣𝑒𝑙.
𝑉𝑑 𝑘
𝑅 𝑅 − 𝑘𝑡 = ln 0.05
95% = (1 − 𝑒 − 𝑘𝑡 )
𝑉𝑑 𝑘 𝑉𝑑 𝑘 ln 0.05
𝑡95% =
95% = 1 − 𝑒 − 𝑘𝑡 −𝐾
95 ln 0.05
𝑒 − 𝑘𝑡 = 1 − =
100 − 0. 69
⁄𝑡1
− 𝑘𝑡
𝑒 = 5% 2

o Proper loading dose?

𝐷𝐿 = 𝐶𝑠𝑠 𝑉𝑑 = 10 × 0.23 × 65000 = 150 𝑚𝑔
o Proper infusion rate for drug?
0.693
𝑅 = 𝐶𝑠𝑠 𝑉𝑑 𝐾 = 10 𝑚𝑔 × 15000 × ( )
𝑡1
2
0.693
= 10 × 15000 × ( )
7
= 14850
o Total body clearance?
𝐶𝑙 𝑇 = 𝑉𝐷 𝐾
= 15000 × 0.09 𝑠 = 1350
❖ An antibiotic has a VD of 10 L & k = 0.2 hr – 1. A SSL, Css = 10 mg/ml. What will
be the infusion rate?
𝑅 = 𝐶𝑠𝑠 𝑉𝑑 𝐾
= 10 × 1000 × 0.2 = 20 𝑚𝑔/ℎ𝑟
❖ An adult male patient (43 years old, 80 kg) is to be given an antibiotic by IV
infusion. According to the Literature, the antibiotic has an elimination t1/2 of 2
hours, a VD of 1.25 L/Kg, & is effective at a plasma drug concentration of 14
mg/L. The drug is supplied in 5 ml ampuls containing 150 mg/ml.
o Recommend a starting infusion rate is milligrams per hour.
𝑅 = 𝐶𝑠𝑠 𝑉𝑑 𝐾
= 14 × 0.693 ⁄2 × 425⁄80 = 458.1 𝑚𝑔/ℎ𝑟
o Blood samples were taken from the patient at 12, 16, 24 hours after the
start of infusion. Plasma drug concentration were as shown below –
t (hr) CP (mg/L)
12 16.1
16 16.3
24 16.5
 Because the plasma drug concentration at 12, 16, & 24 hours were same, so
the steady state concentration reached. So, the average 𝐶𝑠𝑠 = 16.3 𝑚𝑔/𝐿.
We know,
𝑅 𝑅
𝐶𝑆𝑆 = =
𝑉𝑑 𝑘 𝐶𝑙𝑇

𝑅 485.1 𝑚𝑔/ℎ𝑟
𝐶𝑙 𝑇 = = = 29.76 L/hr
𝐶𝑆𝑆 16.3 𝑚𝑔/𝐿

❖ What are some of the complications involved with IV infusion?

Ans: There are some complications involved with IV infusion. They are –
▪ Infiltration – Infiltration is the infusion of fluid and/or medication outside the
intravascular space, into the surrounding soft tissue. Generally caused by poor
placement of a needle or angiocath outside of the vessel lumen. Clinically, you
will notice swelling of the soft tissue surrounding the IV, and the skin will feel
cool, firm, and pale. Small amounts of IV fluid will have little consequence, but
certain medications even in small amounts can be very toxic to the surrounding
soft tissue.
▪ Hematoma - A hematoma occurs when there is leakage of blood from the vessel
into the surrounding soft tissue. This can occur when an IV Angio catheter
passes through more than one wall of a vessel or if pressure is not applied to the
IV site when the catheter is removed. A hematoma can be controlled with direct
pressure and will resolve over the course of 2 weeks.
▪ Air Embolism – Air embolism occurs as a result of a large volume of air
entering the patient's vein via the I.V. administration set. The I.V. tubing holds
about 13 CCs of air, and a patient can generally tolerate up to 1 CC per kilogram
of weight of air; small children are at greater risk. Air embolisms are easily
prevented by making sure that all the air bubbles are out of the I.V. tubing;
fortunately, it is an extremely rare complication.
▪ Phlebitis – Phlebitis and thrombophlebitis occur more frequently. Phlebitis is
inflammation of the vein which occurs due to the pH of the agent being
administered during the administration of the I.V, while thrombophlebitis refers
to inflammation associated with a thrombus. Both are more common on the
dorsum of the hand than on the antecubital facia and may occur especially in
hospitalized patients where an I.V. may be in for several days, where use of an
Angio catheter, as opposed to a needle, can increase the risk of phlebitis, as the
metal needle is less irritating to the endothelium. (Needles are generally used
for short term IV access of less than three hours, while angiocaths are used for
longer periods of time.) The infuscate itself may cause phlebitis and may be
irritating to the skin. Older patients are also more susceptible to phlebitis.
▪ Extravascular drug administration – Extravascular injection of a drug may
result in pain, delayed absorption and/or tissue damage (if the pH of the agent
being administering is too high or too low). If large volumes have been injected
and the skin is raised and looks ischemic, then 1% procaine should be infiltrated.
Procaine is a vasodilator, which will improve the blood supply both to the area
and improve venous drainage away.
 ▪ Intraarterial injection – An intraarterial injection occurs rarely, but is much
more critical. The most important measure is prevention, by making sure that
the needle is inserted in a vein. Remember that veins are more superficial than
arteries. If you cannulate an artery, there should be a pumping of bright red
blood back into your angiocath, which would not be seen when you cannulate a
vein. Intraarterial injection frequently causes arterial spasm and eventual loss of
limb, usually from gangrene. Intraarterial injection is rarer, but as threatening.

❖ What is the main reason for giving a drug by slow IV infusion?

Ans:
➢ In case of IV infusion, when drug is administered rapidly, it tends to increase
the volume of the blood. As a result, hypervolemia may occur, thereby slowly
infused.
➢ Slow IV infusion may be used to avoid side effects due to rapid drug
administration. E.g., intravenous immune globulin may cause a rapid fall in
blood pressure when infused rapidly.
➢ Some antisense drug injected rapidly by IV to the body, it causes a rapid fall in
blood pressure.
➢ The rate of infusion is particularly important in administering anti-arrhythmic
agents in patients.
➢ The rapid IV bolus injection of many drugs that follow the pharmacokinetic of
multi-compartmental models, may cause an adverse response due to the initial
high drug concentration. E.g., if Heparin is injected or infused at a faster rate,
cardiac arrest may arise.

Dose Adjustment in Renal & Hepatic Disease

Uremia
Acute disease or trauma to the kidney can cause uremia, in which glomerular filtration is
impaired or reduced, leading to accumulation of excessive fluid & blood nitrogenous
products in the body.
Pharmacokinetic Considerations
Uremic patients may exhibit pharmacokinetic changes in bioavailability, such as VD,
clearance.
Common causes of Kidney failure
Pyelonephritis Inflammation & deterioration of the pyelonephrons due to
infection, antigens or other idiopathic causes.
Hypertension Chronic overloading of the kidney with fluid & electrolytes may
lead to kidney insufficiency.
Diabetes mellitus The disturbance of sugar metabolism & acid – base balance may
lead to or predispose a patient to degenerative renal disease.
 Nephrotoxic drugs/ Certain drugs taken chronically may cause irreversible kidney
metals damage – e.g., the aminoglycosides, phenacetin, & heavy metals,
such as mercury & lead.
Hypovolemia Any condition that causes a reduction in renal blood flow will
eventually lead to renal ischemia & damage.
Neophroallergens Certain compounds may produce an immune type of sensitivity
reaction with nephritic syndrome – e.g., quartan malaria
nephrotoxic serum.

Dose adjustment Based on Drug Clearance

∞
Methods based on drug clearance try to maintain the desired 𝐶𝑎𝑣 after multiple oral doses/
multiple IV bolus injections as total body clearance, ClT changes,
∞
Calculation for, 𝐶𝑎𝑣 ,
∞ 𝐹𝐷0
𝐶𝑎𝑣 = [z = dose interval]
𝐶𝑙𝑇 𝑍

For patients with a uremic condition or renal impairment, total body clearance of the uremic
patient will change to a new value, 𝐶𝑙𝑈
𝑇.

∞
𝐷0𝑁 𝐷0𝑈
𝐶𝑎𝑣 = =
𝐶𝑙𝑁
𝑇𝑍
𝑁 𝐶𝑙𝑈
𝑇𝑍
𝑈

(Normal) (Uremic)
𝐷0𝑁 𝐶𝑙𝑈
𝑇𝑍
𝑈
𝐷0𝑈 =
𝐶𝑙𝑁𝑇𝑍
𝑁

If dose interval is constant,

𝐷0𝑁 𝐶𝑙𝑈
𝑇
𝐷0𝑈 = 𝑁
𝐶𝑙 𝑇
Creatinine
It is an endogenous substance formed from creatine phosphate during muscle metabolism.
Creatinine production varies with the age, weight & gender of the individual. In humans,
creatinine is filtered mainly at the glomerulus, with no tubular reabsorption.
Blood Urea Nitrogen (BUN)
It is a commonly used clinical diagnostic laboratory test for renal disease. Urea is the end of
product of protein catabolism & is excreted through the kidney. Normal BUN levels range
from 10 – 20 mg/dl. Higher BUN levels generally indicate the presence of renal disease.
Creatinine Clearance
Creatinine clearance may be defined as the rate of urinary excretion of creatinine/ serum
creatinine. Creatinine clearance can be calculated directly by determining the patient’s serum
creatinine concentration & the rate of urinary excretion of creatinine.
 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑢𝑟𝑖𝑛𝑎𝑟𝑦 𝑒𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒
𝐶𝑙𝑐𝑟 =
𝑆𝑒𝑟𝑢𝑚 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒
Creatinine clearance should be based on ideal body weight.
LBW
Lean body weight, based on the patient’s height & actual (total) body weight.
𝐿𝐵𝑊 (𝑚𝑎𝑙𝑒𝑠) = 50 𝑘𝑔 + 2.3 𝑘𝑔 𝑓𝑜𝑟 𝑒𝑎𝑐ℎ 𝑖𝑛𝑐ℎ 𝑜𝑣𝑒𝑟 5 𝑓𝑡.
𝐿𝐵𝑊 (𝑓𝑒𝑚𝑎𝑙𝑒) = 45.5 𝑘𝑔 + 2.3 𝑘𝑔 𝑓𝑜𝑟 𝑒𝑎𝑐ℎ 𝑖𝑛𝑐ℎ 𝑜𝑣𝑒𝑟 5 𝑓𝑡.
Obese patient
Patient more than 20% over ideal body weight.
Calculation of Creatinine Clearance from Serum Creatinine Concentration
Serum creatinine concentration 𝐶𝑐𝑟 , is related to creatinine clearance & is measured routinely.
Therefore, 𝐶𝑙𝑐𝑟 , is most often estimated from the patient’s 𝐶𝑐𝑟 . Several methods are available
for the calculation creatinine clearance from the serum clearance concentration.
Adults
The method of Crock croft & Gault (1976) shown in an equation, that is used to estimate
creatinine clearance from serum creatinine concentration. This method considers both the age
& the weight of the patient.
For males,
[140 − 𝑎𝑔𝑒 (𝑦𝑒𝑎𝑟) × 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)]
𝐶𝑙𝑐𝑟 =
72 (𝐶𝑐𝑟 )
For females, 90% of the 𝐶𝑙𝑐𝑟 value obtained in males.
Children
0.55 𝑏𝑜𝑑𝑦 𝑙𝑒𝑛𝑔𝑡ℎ (𝑐𝑚)
𝐶𝑙𝑐𝑟 =
𝐶𝑐𝑟
Where 𝐶𝑙𝑐𝑟 is given in ml/min/ 1.73 m2.
Nomograms
Nomograms are charts available for use in estimating dosage regimens in uremic patients.
The nomograms may be based on serum creatinine concentrations, patient data (height, wt,
age, gender) & the pharmacokinetics of the drug.
Most methods for dose adjustment in renal disease assume that non – renal elimination of the
drug is not affected by renal impairment & that the remaining renal excretion rate constant in
the uremic patient is proportional to the product of a constant & the creatinine clearance,
𝐶𝑙𝑐𝑟 .
𝐾𝑢 = 𝐾𝑛𝑟 + ∝ 𝐶𝑙𝑐𝑟
 Pharmacokinetics of Drug Absorption

Pharmacokinetic – Pharmacokinetic is the science of the kinetics of drug absorption,

distribution & elimination (i.e., excretion & metabolism). The description of distribution &
elimination is often termed drug disposition.

Drug release Absorption Drug in system

& dissolution circulation Drug in tissues

Elimination

Excretion & Pharmacologic or

Metabolism Clinical Effect

Figure – Relationship between Absorption & Clinical effect

The variability in systemic drug absorption can be minimized to some extent by proper
biopharmaceutical design of the dosage form to provide predictable & reliable drug therapy.
The systemic drug absorption from the gastrointestinal (GI) tract or from any other
extravascular site is dependent on –
✓ The physiochemical properties of the drug
✓ Dosage form used
✓ Anatomy & physiology of the absorption site.
In pharmacokinetics, the overall rate of drugs absorption may be described as either a first
order or zero order input process.

Absorption Elimination
DGI DB VD DE

𝑑𝐷
The rate of change in the amount of drug in the body, 𝐵⁄𝑑𝑡, is dependent on the relative
rate of drug absorption & elimination. The net rate of drug accumulation in the body at any
time is equal to the rate of drug absorption less the rate of drug elimination, regardless of
whether absorption is “0” – order or first order.

𝑑𝐷𝐵⁄ 𝑑𝐷𝐺𝐼 𝑑𝐷𝐸

𝑑𝑡 = −
𝑑𝑡 𝑑𝑡
Here, 𝐷𝐺𝐼 is amount of drug in the gastrointestinal tract & 𝐷𝐸 is amount of drug eliminated.
During the absorption phase of plasma time curve, the rate of drug absorption is greater than
the rate of drug elimination.
 𝑑𝐷𝐺𝐼 𝑑𝐷𝐸
> -----(1)
𝑑𝑡 𝑑𝑡

At the peak drug concentration in the plasma, the rate of drug absorption just equals the rate
of drug elimination & there is no net change in the amount of drug in the body,
𝑑𝐷𝐺𝐼 𝑑𝐷𝐸
= ---------(2)
𝑑𝑡 𝑑𝑡

Immediately after the time of peak drug absorption, some drug may still be at the absorption
site (i.e., in the GI tract or other site of administration). However, the rate of drug elimination
at this time is faster than the rate of absorption as represented by the post absorption phase –
𝑑𝐷𝐺𝐼 𝑑𝐷𝐸
<
𝑑𝑡 𝑑𝑡
When the drug at the absorption site becomes depleted the rate of drug absorption approaches
𝑑𝐷𝐺𝐼
zero, or = 0. The plasma level time curve then represents only the elimination of drug
𝑑𝑡
from the body, usually a first order process. Therefore, during the elimination phase the rate
of change in the amount of drug in the body is described as a first order process.
𝑑𝐷𝐵 𝑑𝐷𝐸
= −
𝑑𝑡 𝑑𝑡
= − 𝑘. 𝐷𝐵

Zero order absorption model –

K0 K
DGI DB VD

Let us consider a drug, that was orally given,

Here,
DGI = Amount of drug in gastro-intestinal tract.
DB = Amount of drug after absorption.
K0 = Absorption rate constant for zero-order process.
K = elimination rate constant for 1st order process.
Zero order drug absorption from the dosing site into the plasma usually occurs when either the
drug is absorbed by a saturable process or a zero-order controlled release delivery system is
used.
In this model, drug in the gastrointestinal tract, DGI is absorbed systemically at a constant rate,
K0. Drug is simultaneously & immediately eliminated from the body by a first order rate
process defined by a first order rate process defined by a first order rate constant, K.
The rate of first order elimination at any time is equal to DB K, the rate of input is simply K0.
Therefore, the net change per unit time in the body can be expressed as,
𝑑𝐷𝐵
= 𝐾0 − 𝑘𝐷𝐵 -------- (1)
𝑑𝑡
𝑑𝑡
Multiply by ,
𝐷𝐵

𝑑𝐷𝐵 𝑑𝑡 𝑑𝑡 𝑑𝑡
× = 𝐾0 . − 𝑘𝐷𝐵 .
𝑑𝑡 𝐷𝐵 𝐷𝐵 𝐷𝐵

𝑑𝐷𝐵 𝑑𝑡
= 𝐾0 . − 𝑘. 𝑑𝑡
𝐷𝐵 𝐷𝐵

Integrate the equation,

𝐾0
𝐷𝐵 = (1 − 𝑒 − 𝑘𝑡 )
𝑘

We know,
𝐷𝐵 = 𝐶𝑃 . 𝑉𝐷
𝐾0
𝐶𝑃 . 𝑉𝐷 = (1 − 𝑒 − 𝑘𝑡 )
𝑘
𝐾0
∴ 𝐶𝑃 = (1 − 𝑒 − 𝑘𝑡 ) -------- (2)
𝑘.𝑉𝐷

The rate of drug absorption is constant until the amount of drug in the gut, DGI, is depleted. The
time for complete drug absorption to occur is equal to DGI/K0. After this time, the drug is no
longer available for absorption from the gut, & equation – 2 is no longer holds. The drug
concentration in the plasma subsequently declines in accordance with a first order elimination
rate process.
First Order Absorption Model –
Although zero – order absorption can occur, absorption is usually assumed to be a first order
process. This model assumes a first order input across the gut wall & first order elimination
from the body.
This model applies mostly to the oral absorption of drugs in solution or rapidly dissolving
dosage (immediate release) forms such as tablets, capsules & suppositories. In addition, drugs
given by intramuscular or subcutaneous aq. Injections may also be described using a first order
process.
In the case of a drug given orally, the dosage form first disintegrates if it is given as a solid,
then the drug dissolves into the fluids of the GI tract. Only drug in solution is absorbed into the
body. The rate of disappearance of drug from the gastrointestinal tract is described by,
𝑑𝐷𝐺𝐼⁄
𝑑𝑡 = −𝑘𝑎 𝐷𝐺𝐼 𝐹
Here,
Ka = 1st order absorption rate constant from GI tract.
F = Fraction of drug that absorbed.
 DGI = Amount of drug in solution in the GI tract at any time t,
Now, we know that,
𝑑𝐷𝐺𝐼⁄ − 𝑘𝑡
𝑑𝑡 = 𝐷0 . 𝑒 [ 𝐷0 = dose of the drug.]

As we know, rate of drug elimination = 1st order process.

𝑑𝐷𝐺𝐼⁄
𝑑𝑡 = 𝑟𝑎𝑡𝑒 𝑖𝑛 − 𝑟𝑎𝑡𝑒 𝑜𝑢𝑡
𝑑𝐷𝐺𝐼⁄
𝑑𝑡 = 𝐹. 𝑘𝑎 . 𝐷𝐺𝐼 − 𝑘. 𝐷𝐵
Here,
F = Fraction of drug absorbed. Systemically, & since the drug in the gastrointestinal
tract also follows a first order decline. (i.e. – the drug is absorbed across the GI wall).
The amount of drug in the gastrointestinal tract at any time “t” is equal to 𝐷0 . 𝑒 − 𝑘𝑡 .
𝑑𝐷𝐺𝐼⁄ − 𝑘𝑡
𝑑𝑡 = 𝐹. 𝑘𝑎 . 𝐷0 . 𝑒 − 𝑘. 𝐷𝐵 ------- (1)

F must be remain 0 – 1.
Here, 1 means drug is fully absorbed
0 means drug is completely unabsorbed.

Equation – 2 multiply with 𝑑𝑡⁄𝐷 we get,

𝐵
− 𝑘𝑡
𝑑𝐷𝐺𝐼⁄ 𝑒
𝑑𝑡 = 𝐹. 𝑘𝑎 . 𝐷0 . 𝐷𝐵 . 𝑑𝑡 − 𝑘. 𝑑𝑡

After integration we get,

𝐹.𝑘𝑎 . 𝐷0
𝐷𝐵 = (𝑒 − 𝑘𝑡 − 𝑒 − 𝑘𝑎𝑡 ) [𝐷𝐵 = 𝐶𝑃 . 𝑉𝐷 ]
(𝑘𝑎 −𝑘)

This is the 1st order absorption equation [showed]

What is Cmax, tmax? How can you get the equation of tmax from 1st order absorption model?
Cmax – After oral dosing, the maximum plasma concentration of drug in systemic circulation
is known as Cmax/ Peak point/ Peak Concentration.
tmax – The time needed to reach the maximum plasma concentration of drug is systemic
circulation after oral dosing is known as tmax.
tmax from first order absorption model –
The tmax is independent of dose & is dependent on the rate constants for absorption, Ka &
elimination K. At Cmax, the rate of drug eliminated. Therefore, the net rate of concentration
change is equal to zero.
As we know,
𝐹.𝑘𝑎 . 𝐷0
∴ 𝐶𝑃 = (𝑒 − 𝑘𝑡 − 𝑒 − 𝑘𝑎𝑡 ) [1st order abs equation].
𝑉𝐷 (𝑘𝑎 −𝑘)

By differentiation we get,
𝐹. 𝑘𝑎 . 𝐷0
∴ 𝐶𝑃 = (− 𝑘𝑒 − 𝑘𝑡 − 𝑘𝑎 𝑒 − 𝑘𝑎𝑡 ) = 0
𝑉𝐷 (𝑘𝑎 − 𝑘)
Or,
𝐹.𝑘𝑎 . 𝐷0
(− 𝑘𝑒 − 𝑘𝑡 − 𝑘𝑎 𝑒 − 𝑘𝑎𝑡 ) = 0
𝑉𝐷 (𝑘𝑎 −𝑘)

Or,
(− 𝑘𝑒 − 𝑘𝑡 + 𝑘𝑎 𝑒 − 𝑘𝑎𝑡 ) = 0
Or,
𝑘𝑒 − 𝑘𝑡 = 𝑘𝑎 𝑒 − 𝑘𝑎𝑡
Add by ln,
ln 𝑘 − 𝑘𝑡 = ln 𝑘𝑎 − 𝑘𝑎 𝑡
Now, t = tmax.
𝑘
ln 𝑘𝑎 − ln 𝑘 ln 𝑎⁄𝑘
𝑡𝑚𝑎𝑥 = =
𝐾𝑎 − 𝑘 𝐾𝑎 − 𝑘
𝑘𝑎⁄
2.3 log 𝑘
𝑡𝑚𝑎𝑥 =
𝐾𝑎 − 𝑘

Give the graphical presentation of first order absorption model.

From the first order absorption model equation we get,
𝐹. 𝑘𝑎 . 𝐷0
∴ 𝐶𝑃 = (− 𝑘𝑒 − 𝑘𝑡 − 𝑘𝑎 𝑒 − 𝑘𝑎𝑡 )
𝑉𝐷 (𝑘𝑎 − 𝑘)
This equation shows that, 𝐶𝑃 is directly proportional to dose, fraction of drug absorbed. The
first order elimination rate constant may be determined from the elimination phase of the
plasma level time curve. At later time intervals, when drug absorption has been completed, i.e.,
𝑒 − 𝑘𝑎𝑡 ≈ 0. Thus, the equation will be,
 𝐹. 𝑘𝑎 . 𝐷0 − 𝑘𝑡
𝐶𝑃 = 𝑒
𝑉𝐷 (𝑘𝑎 − 𝑘)
𝐹. 𝑘𝑎 . 𝐷0
𝑂𝑟, ln 𝐶𝑃 = ln − 𝑘𝑡
𝑉𝐷 (𝑘𝑎 − 𝑘)
𝐹. 𝑘𝑎 . 𝐷0 𝑘𝑡
𝑂𝑟, log 𝐶𝑃 = log −
𝑉𝐷 (𝑘𝑎 − 𝑘) 2.3
With this equation, a graph constructed by plotting log 𝐶𝑃 vs time will yield a straight line with
𝑘𝑡
a slope of − .
2.3

Log time –
In some individuals, absorption of drug after a single oral dose does not start immediately, due
to some physiologic factors as – stomach emptying time, intestinal motility, intake of drug
immediately after heavy meal, ulcer. The time delay prior to the commencement of first order
drug absorption is known as lag time.
The lag time for a drug may be observed of the two residual lines obtained by feathering the
oral absorption plasma level time curve intersect at a point greater than, t = 0 on the x – axis.
The time at the point of intersection on the x – axis is the lag time.
Flip – Flop of Ka & K –
In pharmacokinetics, flip – flop phenomenon happens when a drug is released at a sustained
rate instead of immediate release, such as sustained – release formulation vs immediate release
formulation or IV.
In flip-flop kinetics, Ka is much slower than k (elimination rate constant). These apparent
differences shift the slope of log 𝐶𝑃 vs time curve in which now the apparent part “k” look
much smaller than it is if the drug is administered IV or by immediate – release formulation.
The part of downward curve becomes a reflection of actual Ka while the upward part of the
curve is the actual representation of k. That “flip – flop” curve is the so called ‘flip-flop’
kinetics.
Example – the “k” obtained after on IV bolus injection of a bronchodilator was 1.72 hr – 1.

Causes of Flip – Flop Characteristics –

Most of the drugs observed to have flip – flop characteristics are drug with fast elimination.
(i.e., 𝑘 > 𝐾𝑎). For drugs that have a large elimination rate constant (K > 0.69 ℎ𝑟 −1 ).
Pharmacokinetics of Oral Absorption

How do you explain that “ka” is often “k”?

A drug with a rate of absorption slower than its rate of elimination will not be able to obtain
optimal systemic drug concentrations to achieve efficacy. Such drugs are generally not
developed into products.
In switching a drug from IV to oral dosing, what are the most important
considerations?
In case of 1st order absorption model, we know –
𝐹. 𝑘𝑎 . 𝐷0
∴ 𝐶𝑃 = (− 𝑘𝑒 − 𝑘𝑡 − 𝑘𝑎 𝑒 − 𝑘𝑎𝑡 )
𝑉𝐷 (𝑘𝑎 − 𝑘)
Drug of IV dose need no absorption, but in oral dose drug must be absorbed, then we will get
the efficacy. So, from this equation we identify “F” that means fraction of drug absorbed.
Here, F ranges for 0 – 1.
If 0, that means no drugs absorbed, no efficacy.
If 1, that means drug is fully absorbed, 100% bioavailability.
So, the main consideration is of “F” next important consideration is uses of proper excipients.
The excipients must be non – toxic, non – irritant & must not hampered the “F”. Next one is
use of proper equipment.
Determination of Ka by plotting precent of Drug unabsorbed versus time on Wagner –
Nelson Method –
After a single oral dose of a drug, the total dose should be completely accounted for in the
amount present in the body, the amount present in the urine, & the amount present in the GI
tract. Therefore, dose (D0) is expressed as follows –
𝐷0 = 𝐷𝐺𝐼 + 𝐷𝐵 + 𝐷𝑢
Let,
Ab = 𝐷𝐵 + 𝐷𝑢 = amount of drug absorbed.
𝐴𝑏 ∞ = Amount of drug absorbed at t = ∞
𝐴𝑏
At any given time, the fraction of drug absorbed =
𝐴𝑏∞
𝐴𝑏
& The fraction of unabsorbed = 1 –
𝐴𝑏∞

The amount of drug excreted at any time “t” can be calculated as, 𝐷𝑢 = 𝑘 𝑉𝐷 [𝐴𝑈𝐶]+
0.

The amount of drug in the body (DB) at any time, = 𝐶𝑃 . 𝑉𝐷

At any time, ‘t’ the amount of drug absorbed (Ab) is,
Ab = 𝐶𝑃 . 𝑉𝐷 + 𝑘 𝑉𝐷 [𝐴𝑈𝐶]+
0

At, t = ∞, 𝐶𝑝∞ = 0 (i.e. – plasma concentration is negligible), & the total amount of drug
absorbed (Ab) is,
𝐴𝑏 = 0 + 𝑘 𝑉𝐷 [𝐴𝑈𝐶]∞
0

The fraction of drug absorbed at any time is,

𝐴𝑏 𝐶𝑃 . 𝑉𝐷 + 𝑘 𝑉𝐷 [𝐴𝑈𝐶]𝑡0
=
𝐴∞
𝑏 𝑘 𝑉𝐷 [𝐴𝑈𝐶]∞0

𝐶𝑃 + 𝑘 𝑉𝐷 [𝐴𝑈𝐶]𝑡0
=
𝑘 [𝐴𝑈𝐶]∞ 0

The fraction unabsorbed at any time “t” is,

𝐴𝑏 𝐶𝑃 + 𝑘 𝑉𝐷 [𝐴𝑈𝐶]𝑡0
1− ∞ =1−
𝐴𝑏 𝑘 [𝐴𝑈𝐶]∞ 0

The drug remaining in the GI tract at any time “t” is,

 𝐷𝐺𝐼 = 𝐷0 . 𝑒 − 𝑘𝑎𝑡
𝐷𝐺𝐼
= 𝑒 − 𝑘𝑎𝑡
𝐷0
𝐷𝐺𝐼 𝑘𝑎𝑡
log = −
𝐷0 2.303
Here,
𝐷𝐺𝐼 𝐴𝑏
log is equal to fraction of drug unabsorbed which is equally same as 1 − . So, the graph
𝐷0 𝐴∞
𝑏
will be,
 19

DRUG ABSORPTION, DISTRIBUTION AND ELIMINATION;

PHARMACOKINETICS

I. DRUG ADMINISTRATION
Often the goal is to attain a therapeutic drug concentration in plasma from which drug
enters the tissue (therapeutic window between toxic concentration and minimal effective
concentration).

A. Enteral Routes

1. Sublingual (buccal)
Certain drugs are best given beneath the tongue or retained in the cheek
pouch and are absorbed from these regions into the local circulation.
These vascular areas are ideal for lipid-soluble drugs that would be
metabolized in the gut or liver, since the blood vessels in the mouth bypass
the liver (do not undergo first pass liver metabolism), and drain directly
into the systemic circulation. This route is usually reserved for nitrates
and certain hormones.

2. Oral
By far the most common route. The passage of drug from the gut into the
blood is influenced by biologic and physicochemical factors (discussed in
detail below), and by the dosage form. For most drugs, two- to five-fold
differences in the rate or extent of gastrointestinal absorption can occur,
depending on the dosage form. These two characteristics, rate and
completeness of absorption, comprise bioavailability. Generally, the
bioavailability of oral drugs follows the order: solution > suspension >
capsule > tablet > coated tablet.

3. Rectal
The administration of suppositories is usually reserved for situations in
which oral administration is difficult. This route is more frequently used
in small children. The rectum is devoid of villi, thus absorption is often
slow.

B. Parenteral Routes

1. Intravenous injection
Used when a rapid clinical response is necessary, e.g., an acute asthmatic
episode. This route allows one to achieve relatively precise drug
concentrations in the plasma, since bioavailability is not a concern. Most
drugs should be injected over 1-2 minutes in order to prevent the
occurrence of very high drug concentrations in the injected vein, possibly
causing adverse effects. Some drugs, particularly those with narrow
therapeutic indices or short half-lives, are best administered as a slow IV
infusion or drip.

2. Intra-arterial injection
Used in certain special situations, notably with anticancer drugs, in an
effort to deliver a high concentration of drug to a particular tissue.
Typically, the injected artery leads directly to the target organ.
 20

3. Intrathecal injection
The blood-brain barrier limits the entry of many drugs into cerebrospinal
fluid. Under some circumstances, usually life-threatening, antibiotics,
antifungals and anticancer drugs are given via lumbar puncture and
injection into the subarachnoid space.

4. Intramuscular injection
Drugs may be injected into the arm (deltoid), thigh (vastus lateralis) or
buttocks (gluteus maximus). Because of differences in vascularity, the
rates of absorption differ, with arm > thigh > buttocks. Drug absorption
may be slow and erratic. The volume of injection, osmolality of the
solution, lipid solubility and degree of ionization influence absorption. It
should not be assumed that the IM route is as reliable as the IV route.

5. Subcutaneous injection
Some drugs, notably insulin, are routinely administered SC. Drug
absorption is generally slower SC than IM, due to poorer vascularity.
Absorption can be facilitated by heat, massage or vasodilators. It can be
slowed by coadministration of vasoconstrictors, a practice commonly used
to prolong the local action of local anesthetics. As above, arm > thigh.

6. Inhalation
Volatile anesthetics, as well as many drugs which affect pulmonary
function, are administered as aerosols. Other obvious examples include
nicotine and tetrahydrocannabinol (THC), which are absorbed following
inhalation of tobacco or marijuana smoke. The large alveolar area and
blood supply lead to rapid absorption into the blood. Drugs administered
via this route are not subject to first-pass liver metabolism.

7. Topical application
a. Eye
For desired local effects.
b. Intravaginal
For infections or contraceptives.
c. Intranasal
For alleviation of local symptoms.
d. Skin
Topical drug administration for skin disorders minimizes systemic
exposure. However, systemic absorption does occur and varies
with the area, site, drug, and state of the skin. Dimethyl sulfoxide
(DMSO) enhances the percutaneous absorption of many drugs, but
its use is controversial because of concerns about its toxicity.
e. Drug patches (drug enters systemic circulation by zero order
kinetics – a constant amount of drug enters the circulation per unit
time).
 21

II. DRUG ABSORPTION

A. Biologic Factors

1. Membrane structure and function

The cell membrane is a semipermeable lipoid sieve containing numerous
aqueous channels, as well as a variety of specialized carrier molecules.
a. For most tissues, passive aqueous diffusion through channels
occurs only for molecules less than 150-200 MW. A notable
exception is the endothelial capillary lining, whose relatively large
pores allow molecules of 20-30,000 to pass. However, the
capillaries of most of the brain lack these large pores.
b. Passive lipid diffusion is probably the most important absorptive
mechanism. Lipid-soluble drugs dissolve in the membrane, and
are driven through by a concentration gradient across the
membrane.
c. Carrier-mediated facilitated transport occurs for some drugs,
particularly those which are analogs of endogenous compounds for
which there already exist specific membrane carrier systems. For
example, methotrexate, an anticancer drug which is structurally
similar to folic acid, is actively transported by the folate membrane
transport system.

2. Local blood flow is a strong determinant of the rate of absorption because

it continuously maintains the concentration gradient necessary for passive
diffusion to occur. For orally administered drugs, remember that the
blood supply draining the gut passes through the liver before reaching the
systemic circulation. Since the liver is a major site of drug metabolism,
this first-pass effect may reduce the amount of drug reaching the target
tissue. In some cases, the first-pass effect results in metabolic activation
of an inert pro-drug.

3. Gastric emptying times vary among patients and contribute significantly to

intersubject variability in drug absorption.

4. Drug binding
Many drugs will bind strongly to proteins in the blood or to food
substances in the gut. Binding to plasma proteins will increase the rate of
passive absorption by maintaining the concentration gradient of free drug.
For many drugs, the gastrointestinal absorption rate, but not the extent of
absorption, is reduced by the presence of food in the gut. Some drugs are
not affected by food, while the absorption of a third group of drugs is
enhanced by food (bile secretion by liver in response to food in GI tract
increases drug absorption). Some drugs are irritating and should be
administered with meals to reduce adverse effects.
 22

B. Physicochemical Factors: pH Partition Theory

1. Background review
The simplest definition of an acid is that it is a substance, charged or
uncharged, that liberates hydrogen ions (H+) in solution. A base is a
substance that can bind H+ and remove them from solution. Strong acids,
strong bases, as well as strong electrolytes are essentially completely
ionized in aqueous solution. Weak acids and weak bases are only partially
ionized in aqueous solution and yield a mixture of the undissociated
compound and ions.

Thus a weak acid (HA) dissociates reversibly in water to produce

hydrogen ion H+ and A-.
HA <-----> H+ + A- (1)

Applying the mass law equation, which demands that concentrations are in
moles per liter, we obtain the following equation:
[H+] [A-] = Ka (2)
[HA]

where Ka is the ionization or dissociation constant of the acid. Since the

ion concentrations are in the numerator, the stronger the acid, the higher
the value of Ka. Similarly, one could derive Kb for a weak base BOH.
Rearranging equation (2) yields the following:
[H+] = Ka [HA] (3)
[A-]

Taking the log of both sides of the equation:

log [H+] = log Ka + log [HA] - log [A-] (4)

And multiplying by -1, we obtain:

-log [H+] = -log Ka - log [HA] + log [A-] (5)

By definition, -log [H+] = pH, and -log Ka = pKa. Thus, we obtain the
important relationships
for acids: pH = pKa + log [A-] (6)
[HA]
for bases: pH = pKa + log [B] (7)
[BH+]

From the pKa, one can calculate the proportions of drug in the charged
and uncharged forms at any pH:
log [A-] = (pH - pKa) (8)
[HA]
[A-] = 10(pH – pKa) (9)
[HA]
[B] = 10(pH-pKb) (10)
[BH+]
pKb = (1-pKa)
 23

2. Ion trapping
The influence of pH on transfer of drugs across membranes.

What does this background review have to do with pharmacology. Plenty!

Most drugs are too large to pass through membrane channels and must
diffuse through the lipid portion of the cell membrane. Nonionized drug
molecules are readily lipid-soluble, while ionized molecules are
lipophobic and are insoluble.

The distribution of a drug across the cell membrane is usually determined

by its pKa and the pHs on both sides of a membrane. The difference of
pH across a membrane influences the total concentration of drug on either
side, since, by diffusion, at equilibrium the concentration of nonionized
drug will be the same on either side.

For example, let's consider the influence of pH on the distribution of a

drug which is a weak acid (pKa = 4.4) between plasma (pH = 7.4) and
gastric juice (pH = 1.4). The mucosa can be considered to be a simple
lipid barrier.

Figure 1
 24

At equilibrium, the concentration of the unionized drug [HA] on either side of lipid
barrier will be the same. Using equation (9), we can calculate the molar ratios of ionized
drug [A-] to [HA] on each side of the membrane.

in plasma:
[A-]
[HA] = 10(7.4 - 4.4) = 103 = 1000

in gastric juice:
[A-]
[HA] = 10(1.4 - 4.4) = 10-3 = .001

Figure 2

The pKa values of certain acidic and basic drugs. Those drugs denoted with an * are
amphoteric. (From Rowland, M., and Tozer, T.N.)
 25

III. DRUG DISTRIBUTION

Once in the blood, drugs are simultaneously distributed throughout the body and
eliminated. Typically, distribution is much more rapid than elimination, is accomplished
via the circulation, and is influenced by regional blood flow.

A. Compartments

1. Central Compartment
The central compartment includes the well-perfused organs and tissues
(heart, blood, liver, brain and kidney) with which drug equilibrates
rapidly.

2. Peripheral Compartment(s)
The peripheral compartment(s) include(s) those organs (e.g., adipose and
skeletal muscle) which are less well-perfused, and with which drug
therefore equilibrates more slowly. Redistribution from one compartment
to another often alters the duration of effect at the target tissue. For
example, thiopental, a highly lipid-soluble drug, induces anesthesia within
seconds because of rapid equilibration between blood and brain. Despite
the fact that the drug is slowly metabolized, however, the duration of
anesthesia is short because of drug redistribution into adipose tissue,
which can act as a storage site, or drug reservoir.

3. Special Compartments
Several special compartments deserve mention. Entry of drug into the
cerebrospinal fluid (CSF) and central nervous system (CNS) is restricted
by the structure of the capillaries and pericapillary glial cells (the choroid
plexus is an exception). The blood-brain barrier limits the success of
antibiotics, anticancer drugs and other agents used to treat CNS diseases.
Drugs also have relatively poor access to pericardial fluid, bronchial
secretions and fluid in the middle ear, thus making the treatment of
infections in these regions difficult.

B. Protein Binding

Many drugs bind to plasma proteins. Weak acids and neutral drugs bind
particularly to albumin, while basic drugs tend to bind to alpha-1-acid
glycoprotein (orosomucoid). Some drugs even bind to red cell surface proteins.

1. Effects on drug distribution

Only that fraction of the plasma drug concentration which is freely
circulating (i.e., unbound) can penetrate cell membranes. Protein binding
thus decreases the net transfer of drug across membranes. Drug binding to
plasma proteins is generally weak and rapidly reversible, however, so that
protein-bound drug can be considered to be in a temporary storage
compartment. The protein concentration of extravascular fluids (e.g.,
CSF, lymph, synovial fluid) is very low. Thus, at equilibrium (when the
concentrations of free drug are equal), the total drug concentration in
plasma is usually higher than that in extravascular fluid. The extent of
protein binding must be considered in interpreting "blood levels" of drugs.
 26

2. Effects on drug elimination

The effects of plasma protein binding on drug elimination are complex.
For drugs excreted only by renal glomerular filtration, protein binding
decreases the rate of elimination since only the free drug is filtered. For
example, the rates of renal excretion of several tetracyclines are inversely
related to their extent of plasma protein binding. Conversely, however, if
drug is eliminated by hepatic metabolism or renal tubular secretion,
plasma protein binding may promote drug elimination by increasing the
rate that that drug is presented for elimination.

3. Tissue binding
Binding to tissue proteins may cause local concentration of drug. For
example, if a drug is bound more extensively at intracellular than at
extracellular sites, the intracellular and extracellular concentrations of free
drug may be equal or nearly so, but the total intracellular drug
concentration may be much greater than the total extracellular
concentration.

C. Apparent volume of distribution (AVD or Vd).

The volume of distribution, or more properly the apparent volume of distribution,
is calculated from measurements of the total concentration of drug in the blood
compartment after a single IV injection. Suppose that we injected someone IV
with 100 mg of a drug, and measured the blood concentration of the drug
repeatedly during the next several hours. We then plot the blood concentrations
(on a log scale) against time, and obtain the following graph:
 27

Figure 3

If the drug is assumed to follow two-compartment kinetics, the initial curvilinear portion
of the data reflects the drug distribution phase, with drug moving from the blood into
tissues. The linear portion of the curve reflects drug elimination. By extrapolation of the
linear portion, we can find the blood concentration at time 0, had mixing between both
compartments been instantaneous; it is 10 mg/ml. We can also calculate Vd, which is
defined as:

Vd = amount of drug injected = 100 mg = 10L

blood concentration at time 0 10 mg/L

Vd does not represent a real volume, but rather indicates the size of the pool of body
fluids that would be required if the drug were distributed equally throughout the body.
Drug concentrations in body compartments will vary according to the physicochemical
properties of the drug. Thus, Vd is a characteristic property of the drug rather than the
patient, although disease states may influence Vd. If binding to plasma proteins is
marked, most of the drug will be maintained within the intravascular compartment and
Vd will be small. If there is extravascular binding, or storage in fat or other tissues, Vd
will be large. For example, digoxin, a hydrophobic drug which distributes into fat and
muscle, has a Vd of 640 liters (in a 70 kg man), approximately nine times the total
volume of the man! The usefulness of the Vd concept will become more apparent when
we discuss pharmacokinetics and perform calculations of blood levels of drugs.

In general, acidic drugs bind to plasma proteins and have small Vds, while basic drugs
tend to bind more extensively to extravascular sites and have larger Vds. Vd may be
influenced by disease states. For example, patients with chronic liver disease have lower
serum albumin concentrations. Plasma protein binding will be reduced, leading to lower
plasma drug concentrations and higher Vds.
 28

IV. DRUG BIOTRANSFORMATION

The body is exposed to a wide variety of foreign compounds, called xenobiotics.

Exposure to some such compounds is unintentional (e.g., environmental or food
substances), while others are deliberately used as drugs. The following discussion of
drug biotransformation is applicable to all xenobiotics, and to some endogenous
compounds (e.g., steroids) as well.

The kidneys are capable of eliminating drugs which are low in molecular weight, or
which are polar and fully ionized at physiologic pH. Most drugs do not fit these criteria,
but rather are fairly large, unionized or partially ionized, lipophilic molecules. The
general goal of drug metabolism is to transform such compounds into more polar (i.e.,
more readily excretable) water soluble products. For example, were it not for
biotransformation to more water-soluble products, thiopental, a short-acting, lipophilic
anesthetic, would have a half-life of more than 100 years! Imagine, without
biotransformation reactions, anesthesiologists might grow old waiting for patients to
wake up.

Most products of drug metabolism are less active than the parent compound. In some
cases, however, metabolites may be responsible for toxic, mutagenic, teratogenic or
carcinogenic effects. For example, overdoses of acetaminophen owe their hepatotoxicity
to a minor metabolite which reacts with liver proteins. In some cases, with metabolism
of so-called prodrugs, metabolites are actually the active therapeutic compounds. The
best example of a prodrug is cyclophosphamide, an inert compound which is metabolized
by the liver into a highly active anticancer drug.

A. Sites of drug metabolism

1. At the organ level

The liver is the primary organ of drug metabolism. The gastrointestinal
tract is the most important extrahepatic site. Some orally administered
drugs (e.g., isoproterenol) are conjugated extensively in the intestinal
epithelium, resulting in decreased bioavailability. The lung, kidney,
intestine, skin and placenta can also carry out drug metabolizing reactions.
Because of its enormous perfusion rate and its anatomic location with
regard to the circulatory system, the lungs may exert a first-pass effect for
drugs administered IV.

2. At the cellular level

Most enzymes involved in drug metabolism are located within the
lipophilic membranes of the smooth endoplasmic reticulum (SER). When
the SER is isolated in the laboratory by tissue homogenation and
centrifugation, the SER membranes re-form into vesicles called
microsomes. Since most of the enzymes carry out oxidation reactions, this
SER complex is referred to as the microsomal mixed function oxidase
(MFO) system.

3. At the biochemical level

Phase I reactions refer to those which convert a drug to a more polar
compound by introducing or unmasking polar functional groups such as -
OH, -NH2, or -SH. Some Phase I products are still not eliminated rapidly,
and hence undergo Phase II reactions involving conjugation of the newly
established polar group with endogenous compounds such as glucuronic
acid, sulfuric acid, acetic acid, or amino acids (typically glycine).
Glucuronide formation is the most common phase II reaction. Sometimes,
 29

the parent drug may undergo phase II conjugation directly. In some cases,
a drug may undergo a series of consecutive reactions resulting in the
formation of dozens of metabolites.
Most phase I MFO biotransformation reactions are oxidative in nature and
require a reducing agent (NADPH), molecular oxygen, and a complex of
microsomal enzymes; the terminal oxidizing enzyme is called cytochrome
P450, a hemoprotein so named because its carbon monoxide derivative
absorbs light at 450 nm. We now know that cytochrome P450 is actually a
family of enzymes which differ primarily with regard to their substrate
specificities. Advances in molecular biology have led to the identification
of more than 70 distinct P450 genes in various species.
The nomenclature of the P450 reductase gene products has become
complex. Based upon their amino acid homologies, the P450 reductases
have been grouped into families such that a cytochrome P450 from one
family exhibits < 40% amino acid sequence identity to a cytochrome P450
in another gene family. Several of the gene families are further divided
into subfamilies, denoted by letters A, B, C, etc. Eight major mammalian
gene families have been defined (see Table 1).

Table 1: Major Cytochrome P450 Gene Families

P450 Gene Characteristic Characteristic Characteristic

Family/Subfamily Substrates Inducers Inhibitor

CYP 1A2 Acetominophen Tobacco Cimetidine

Estradiol Char-Grilled Meats Amiodarone
Caffeine Insulin Ticlopidine

CYP 2C19 Diazepam, Omeprazole Prednisone Cimetidine

Progesterone Rifampin Ketoconazole
Omeprazole

CYP 2C9 Tamoxifen Rifampin Fluvastatin

Ibuprofen Secobarbital Lovastatin
Fluoxetine Isoniazid

CYP 2D6 Debrisoquine Dexamethasone? Cimetidine

Ondansetron Rifampin? Fluoxetine
Amphetamine Methadone

CYP 2E1 Ethanol Ethanol Disulfiram

Benzene Isoniazid Water Cress
Halothane

CYP 3A4, 5, 7 Cyclosporin Barbiturates Cimetidine

Clarithromycin Glucocorticoids Clarithromycin
Hydrocortisone Carbamazepine Ketoconazole
Vincristine St. John’s Wort Grapefruit Juice
Many, many others Many others
 30

B. Enzyme Induction
An interesting and important feature of the cytochrome P450 mixed function
oxidase system is the ability of some xenobiotics to induce the synthesis of new
enzyme. Microsomal enzyme induction is a complex and poorly understood
process associated with an increase in liver weight, proliferation of the SER, and
synthesis of P450 enzymes. For example, phenobarbital induces the P450IIB
subfamily, while polycyclic aromatic hydrocarbons (e.g., found in cigarette
smoke or charcoal broiled foods) induce the P450IA subfamily; these and other
inducers are listed in Table 1, above. Obviously, the dose and frequency of drug
administration required to achieve therapeutic drug concentrations in blood may
vary enormously from person to person, depending upon the degree of exposure
to microsomal inducers.

For example, consider patients who routinely ingest barbiturates or tranquilizers

(P450 inducers) who must, for medical reasons, be treated with warfarin or
dicumarol (oral anticoagulants). Because of a faster rate of drug metabolism, the
dose of warfarin will need to be high. If the patient should for some reason
discontinue the barbiturates, the blood level of warfarin will rise, perhaps leading
to a bleeding disorder.

C. Enzyme Inhibition
Relatively few xenobiotics are known to inhibit microsomal enzymes. Some
drugs are used therapeutically because they inhibit specific enzyme systems (e.g.,
monoamine oxidase inhibitors for depression, xanthine oxidase inhibitors for
gout, etc.). Sometimes such drugs are not totally specific and inhibit other
enzyme systems to some extent. However, cimetidine, a widely used anti-ulcer
drug, is an important, potent inhibitor of microsomal drug metabolism which
retards the metabolism of many other drugs, including warfarin and similar
anticoagulants, theophylline and caffeine, phenobarbital, phenytoin, carba-
mazepine, propranolol, diazepam, and chlordiazepoxide. Other inhibitors are
erythromycin and ketonazole. You will encounter these drugs later in the course.
Grapefruit juice also inhibits cytochrome P450.
 31
Table 2: Drug Biotransformation Reactions (Goodman & Gilman, 7th edition, pp. 16-17)
 32

Figure 4

(Goodman & Gilman, 8th edition, p. 16.)

V. DRUG ELIMINATION
The kidney is the most important organ for the excretion of drugs and/or their
metabolites. Some compounds are also excreted via bile, sweat, saliva, exhaled air, or
milk, the latter a possible source of unwanted exposure in nursing infants. Drug
excretion may involve one or more of the following processes.

A. Renal Glomerular Filtration

Glomeruli permit the passage of most drug molecules, but restrict the passage of
protein-bound drugs. Changes in glomerular filtration rate affect the rate of
elimination of drugs which are primarily eliminated by filtration (e.g., digoxin,
kanamycin).

B. Renal Tubular Secretion

The kidney can actively transport some drugs (e.g., dicloxacillin) against a
concentration gradient, even if the drugs are protein-bound. (Actually, only free
drug is transported, but the protein-drug complex rapidly dissociates.) A drug
called probenecid competitively inhibits the tubular secretion of the penicillins,
and may be used clinically to prolong the duration of effect of the penicillins.

C. Renal Tubular Reabsorption

Many drugs are passively reabsorbed in the distal renal tubules. Reabsorption is
influenced by the same physicochemical factors that influence gastrointestinal
absorption: nonionized, lipid-soluble drugs are extensively reabsorbed into
 33

plasma, while ionized and polar molecules will remain in the renal filtrate and be
excreted via urine. Thus, as in the gut, urine pH plays an important role, as does
urine volume. Urine pH may vary widely from 4.5 to 8.0, may be influenced by
diet, exercise, or disease, and tends to be lower during the day than at night. It is
sometimes clinically useful, particularly in drug overdose cases, to alter the pH of
the urine (of the patient). For drugs which are weak acids, urine alkalinization
favors the ionized form and promotes excretion. Alternatively, acidification
promotes the renal clearance of weak bases.

D. Biliary Excretion
Comparatively little is known about hepatic drug elimination. Many drugs and
metabolites are passed into the small intestine via bile and may undergo
enterohepatic cycling. Recent studies have attempted to interrupt enterohepatic
cycling of drugs, pesticides and heavy metals through the oral administration of
non-absorbable, nonspecific adsorbents such as charcoal or cholestyramine. The
results, generally a decrease in drug half-life, have been surprising in that they
suggest that many more drugs undergo enterohepatic cycling than previously
suspected.

VI. PHARMACOKINETICS
Pharmacokinetics is concerned with the variation in drug concentration with time as a
result of absorption, distribution and elimination.

A. The time course of drug action depends on:

1. Drug dose, route of administration, rate and extent of absorption,

distribution rate (particularly to site of action) and rate of elimination.

2. The minimum effective concentration and concentration-effect

relationship.

Consideration of the time course of drug action is important since usually it is

necessary to maintain a certain concentration of drug at its site of action for a
finite period of time.
 34

Figure 5

Figure 5 shows the change in plasma drug concentration [D]p with time after
administration of a single oral dose. The interrupted horizontal lines show the
minimum effective concentration (MEC) and toxic concentration (TC). A
therapeutic effect can be expected only when plasma level is above the MEC and
below the TC.

Since effect usually is proportional to plasma (or tissue) concentration, the

objective of therapy is to attain and maintain the needed plasma concentration for
the period needed, whether this is days or years. To do this, one need understand
something about pharmacokinetics.

Most of the pharmacokinetic concepts we will deal with describe the behavior of
a simple one-compartment model in which drug equilibrates so rapidly in the
entire volume that the dominant factors are the rates of absorption (input) and
elimination (output).

Figure 6

In this model kin describes the rate of input and kout the rate of output. When these rates
are equal, the amount and concentration in the compartment are constant.
 35

Figure 7

Models of drug distribution and elimination.

The effect of adding drug to the blood by rapid intravenous injection is represented by expelling a known amount of
the agent into a beaker. The time course of the amount of drug in the beaker is shown in the graphs at the right. In
the first example (A), there is no movement of drug out of the beaker, so the graph shows only a steep rise to
maximum followed by a plateau. In the second example (B), a route of elimination is presented and the graph
shows a slow decay after a sharp rise to a maximum. Because the level of material in the beaker falls, the "pressure"
driving the elimination process also falls, and the slope of the curve decreases, approaching the steady state
asymptotically. This is an exponential decay curve. In the third model (C), drug placed in the first compartment
(blood) equilibrates rapidly with the second compartment (extravascular volume) and the amount of drug in "blood"
declines logarithmically to a new steady state. The fourth model (D), illustrates a more realistic combination of
elimination mechanism and extravascular equilibration. The resulting graph shows an early distribution phase
followed by the slower elimination phase. These curves can be linearized by plotting the logarithm of the amount of
drug against time.
 36

B. First order and zero order processes

The rate of absorption or elimination can be expressed either in terms of a half-
time (t1/2, the time required for 50% to be absorbed or eliminated, or a rate
constant (k), the fraction absorbed or eliminated per unit time. For absorption we
usually use the symbols ka and t1/2a, and for elimination ke and t1/2e.

If either value is known, the other can be calculated from the relationships:

k = 0.693/t1/2 t1/2 = 0.693/k

For most sites of administration drug absorption follows first order kinetics and
for most routes of elimination the process also is first order or exponential.

1. First order kinetics

A first order process is one by which a constant fraction of the drug
present will be absorbed or eliminated in a unit of time.

For a drug eliminated by a first order process, a plot of plasma

concentration after the last dose as a function of time will give a straight
line on semilog paper. First order elimination is depicted graphically in
Figure 8, below.

Figure 8

When the volume of distribution (Vd = total body store/plasma

concentration) is known, the CLEARANCE of a drug can be found from:

Clearance = Vd . ke
 37

2. Zero order kinetics

Zero order kinetics describe processes in which a constant amount of drug
is absorbed or eliminated per unit time. A constant rate intravenous
infusion is one example of a zero order process.

For most drugs, absorption and elimination follow first order kinetics because the
drug concentration is not sufficient to saturate the mechanism for absorption or
elimination. If the process saturates, then zero order kinetics apply. For some
drugs, elimination kinetics are dose-dependent (or more correctly, concentration-
dependent). As the plasma level increases, the value of t1/2e increases; the plasma
concentration increases disproportionately with increases in dose, and finally,
elimination rate becomes independent of plasma concentration.

C. The time course of change in plasma concentration

When a drug is administered in a single dose, and when absorption and
elimination are first order processes, it is reasonable to have some idea of the
effects of three variables (t1/2a, dose and t1/2e) on the time-course of change in
plasma concentration, as shown in Figure 9.

1. More rapid absorption will increase the peak plasma concentration,

decrease the latency (time required to attain drug effect) and decrease the
duration of effect.
2. An increase in dose will also decrease latency and increase peak plasma
concentration and increase duration of effect.
3. More rapid elimination will decrease peak plasma concentration and
duration of effect.

Figure 9
 38

D. The Plateau Effect

When repeated doses of a drug are given at sufficiently short intervals, and
elimination is a first order process, the plasma concentration (and total body store)
will increase to a steady value or plateau. The same thing will happen if a drug is
administered as a constant rate intravenous infusion (zero order in) and eliminated
by a first order process. The latter case may be simpler to consider first.

During constant IV infusion, the total body store increases exponentially to a

steady value. The half-time for the change in plasma concentration is equal to
t1/2e. This means that 50% of the final concentration is attained in one t1/2e, 75%
in two and 87.5% in three. 90% of the final value is attained in 3.3t1/2e; this is a
useful fact to remember.

With intermittent dosing, unless the dose interval is quite long compared to t1/2e,
accumulation and the increase in plasma concentration will follow a similar time-
course, but there will be fluctuations in plasma level between doses. The shorter
the dose interval and the smaller the dose, the smaller will be the fluctuations.

Figure 10
 39

E. Some Sometimes Useful Points

The approximate total body storage (TBS) of drug is equal to 1.44 times the
amount administered per t1/2e. If one can estimate the TBS, and the Vd is known,
one can calculate the average plasma concentration. If one knows the desired
"plasma level" and Vd, one can estimate the dose needed to attain that value.

For drugs that are rapidly absorbed, a short t1/2e may cause the plasma
concentration to fall below MEC between doses unless the dose is large. If the
dose is large, the peak plasma concentration may exceed the TC. Avoidance of
toxicity and maintenance of a steady effect are easier with drugs for which t1/2e is
relatively long.

Sometimes it is desirable to attain the drug effect quite rapidly; to do this it may
be necessary to give a loading dose. A loading dose is larger than the usual
maintenance dose. An approximate relationship between loading dose (D1),
maintenance dose (D) and dose interval (T) is given by:

D1 = 1.4 t1/2e (D/T)

(The loading dose often is given in fractions at intervals shorter than the usual
dose interval.)

F. Factors Which Modify Dose and Dose Interval

1. Altered absorption.
2. Altered elimination
3. Altered volume of distribution.

The presence of food in the GI tract and altered GI motility and absorptive
properties can influence the rate and extent of absorption. For parenteral
administration, changes in local perfusion can have the same effect.

Drug elimination can be strongly influenced by disease. Altered hepatic perfusion

(as in shock or heart failure) and altered renal function cause frequent problems.
The change in renal clearance of drug can be estimated from the endogenous
creatinine clearance (or, less accurately, from serum creatinine or BUN).

G. Pharmacokinetic Parameters

1. Apparent volume of distribution (Vd or AVD)

Let D = amount of drug administered IV
Let C = plasma drug concentration at time 0, had mixing between
compartments been instantaneous

Then, Vd = D/C
 40

2. Half-time of elimination (t1/2e)

The time it takes to eliminate half of the circulating drug. (See Figure 8.)

3. Elimination rate (Er) and elimination rate constant (ke)

These parameters describe, in mathematical terms, the elimination of a

drug by all processes (i.e., renal + hepatic + all other).

a. Zero order elimination

Implies that a fixed number of drug molecules are eliminated per
unit time. Ethanol is a good example. In this case, Er = ke.

b. First order elimination

Implies that a constant fraction of the drug molecules are
eliminated per unit time. This is the case for most drugs. In this
case, ke is simply defined as the slope of decline in plasma drug
concentration, i.e.,

ke = delta y/delta x = ln (2) = 0.693

t1/2e t1/2e

Once again, look at Figure 8 in the syllabus and this relationship

should be apparent.
In this case, Er = dD/dt = -ke/D.

4. Clearance (Cl)
Clearance refers to the volume of plasma cleared of drug (by all processes)
per unit time, i.e.,

Cl = ke x Vd

5. Absorption rate constant (ka)

Just as elimination can occur in zero order or first order fashion, so too can
absorption from the gut or an injection site occur by zero order or first
order kinetics. Typically, absorption follows first order kinetics.

The exceptions are generally limited to depot or slow release preparations

(e.g., slow release insulin injections), in which case zero order kinetics
apply. For IV drug administration, zero order kinetics also apply, since a
given number of drug molecules are infused per unit time.

6. Bioavailability (F)
The rate and extent to which an active drug ingredient is absorbed and
becomes available at the site of drug action. By definition, for intravenous
drugs, F = 1. Oral bioavailability can be determined by comparing the
area under the curve (AUC) (of the plot of plasma drug concentration vs.
time) after an oral dose to that for an intravenous dose, i.e.,

F = AUCoral/AUCIV
 41

7. Relative Bioavailability
The extent to which an oral drug product (e.g., a generic drug product) is
absorbed in comparison to the trade name, or currently marketed drug
product. This is usually determined by comparing the area under the
curve (AUC) (of the plot of plasma drug concentration vs. time) of the
new product to that of the trade name product, i.e.,

Relative F = AUCgeneric/AUCtrade name

For many drugs, however, regulatory decisions concerning generic drugs

are based upon the ability of the generic product to achieve the same bmax
(peak blood concentration) and tmax (time at which bmax occurs).

H. Kinetics following a single drug dose

1. Intravenous
The curve is triphasic, with a rapid peak, decline (the distribution phase)
and a slow elimination phase from which ke can be calculated.

2. Subcutaneous or intramuscular
The drug takes a finite time to reach the circulation. The levels of drug in
blood continue to rise until the number of drug molecules being eliminated
per unit time exceeds that being absorbed per unit time. In general, the
entire dose will reach the circulation, i.e., bioavailability (F) = 1.

3. Oral
The pattern is similar to that of SC or IM, but usually bmax is lower, and
tmax occurs later.

I. Steady State Kinetics

The administration of a drug at intervals shorter than about 4 elimination half-
times will result in accumulation of the drug in the body. The accumulation will
continue until the amount of drug absorbed per unit time equals the amount of
drug eliminated per unit time, at which time a plateau, or steady state
concentration (Css) will be reached.

1. Constant IV infusions
For constant IV infusions, zero order absorption, and first order
elimination apply. At equilibrium, input = output.

i.e., ka = Cl x Css = Vd x ke x Css

thus, Css = ka/(Vd x ke)

The important principle here is that Css is regulated only by Ka and ke.
Therefore, to double Css, simply double the drug infusion rate (which is
usually in units of mg/hr).
 42

Note: There are important exceptions where doubling the dose does not
result in a doubling of Css. In these cases, "dose-dependent kinetics"
apply; in this course, we will not cover the mathematics of dose-dependent
kinetics. Most dose-dependent situations occur because one or more of
the processes involved in drug absorption, distribution, metabolism, or
excretion show saturability, a condition in which the rate of a given
process increases or decreases with the drug concentration. For example,
the active tubular secretion of penicillin is saturable; thus, as the dose is
increased, ke will decrease. As another example, the first pass hepatic
metabolism of propranolol is saturable; thus, as the oral dose is increased,
the effective ka will increase.

2. Repeated oral doses

In this case, ka is influenced by the bioavailability (F) of the drug, the
interval between drug doses, and the dose itself. Thus,

ka = F x Dm/T,
where Dm = maintenance dose (e.g., in mg)
T = dose interval (e.g., in hours)
F = bioavailability (the fraction absorbed)

Note that the units of ka are mg/hr, just as in the case of the IV situation
described above.

At steady state, input = output, i.e.,

ka = F x Dm/T = Css x Vd x ke

Rearranging this equation, we obtain:

Css = Dm F/(Vd x ke x T) = (1.44 x Dm x F x t1/2e) /(T x Vd)

(Note: 1.44 is simply the reciprocal of .693, i.e. 1/0.693)

This last equation is one which you must know in order to calculate
maintenance doses and dose intervals. Once you have decided what the
target Css should be, this equation will permit you to calculate dose and
dose interval. Note, however, that there is no unique dose (Dm) and dose
interval (T), since these are two variables in the same equation. Thus, it is
possible that different combination of Dm and T could be used to achieve
the same Css.

3. Initial oral loading dose

When a prompt drug response is needed, e.g., with the use of theophylline
to treat an acute asthma episode, it is often useful to initiate treatment with
a single "loading dose" which is larger than the typical maintenance dose
of the drug. The loading dose allows one to achieve plasma drug
concentrations above the minimum effective concentration (MEC)
quickly.
 43

The loading dose may be calculated from the equation:

D1 = (Vd x Css)/F

where D1 = loading dose and F = bioavailability.

Note that when the loading dose is administered parenterally

(intravenous), F can be considered to be equal to 1.

This equation implies that D1 equals the amount of drug in the body at the
desired therapeutic plasma level.

4. Second loading dose

In practice, one often administers an initial loading dose, allows some time
to pass, and then obtains a measurement of the plasma drug concentration.
Sometimes (hopefully) the measured value will fall in the desired range, in
which case no additional loading dose is required and one can proceed
with "maintenance" therapy. Other times, however, the measured serum
drug concentration will be found to be too low, in which case a second
loading dose may need to be administered. How does one calculate this
second, smaller loading dose?

The only parameter which needs to be altered in the original loading dose
equation is Css, from which one must subtract the actual measured value.
In other words:

D2 = (Vd) (Css - Cact)

F

where D2 = the second loading dose

Css = the desired steady state concentration
F = bioavailability
Cact = the actual measured serum drug concentration

Thus, D2 equals the dose of drug required to alter the serum drug
concentration from the observed value to the desired value.
 44

Table 3 Pharmacokinetic and Pharmacodynamic Parameters for Selected Drugs*

Oral Urinary Bound In Volume of

Avail. Excret. Plasma Clearance Distrib. Half-Life Effective+ Toxic+
Drug (percent) (percent) (percent) (mL/min/70kg) (L/70 kg) (hours) Concentrations Concentrations
____________________________________________________________________________________________________________________________________
Acetaminophen 63+5 3+1 0-15 350+100 67+8 2.0+0.4 10-20 lg/mL >350 lg/mL
Amikacin 98 4 77+14 15+6 2.3+0.4
Amoxicillin 93+10 52+15 18 370+90 29+13 1.0+0.1
Ampicillin 25-70 90+8 18 270+50 20+5 1.3+02
Aspirin 68+3 1.4+1.2 49 650+80 11+2 0.25+0.3 See Salicylic Acid
Carbamazepine >70 <1 82+5 89+37 98+26 15+5 6.5+3.0 lg/mL >10 lg/mL
Cephalexin 90+9 96 14+3 300+80 18+2 0.90+0.18
Cephalothin 52 71+3 470+120 18+8 0.57+0.32
Chloramphenicol 75-90 5+1 53+5 250+120 64 2.7+08
Chlordiazepoxide 100 <1 96.5+1.8 26+4 21+2 9.9+2.5 >0.7 lg/mL
Cimetidine 62+6 77+6 19 840+210 150+70 2.1+1.1 >1.0 lg/mL
Clonidine 75+4 62+11 210+84 150+30 8.5+2.0 0.5-1.5 ng/mL
Diazepam 100 <1 98+7 27+4 77+20 20-90 >600 ng/mL
Digitoxin >90 33+15 90+2 3.2+1.6 36+13 6.9+2.7 days >10 ng/mL >35 ng/mL
Digoxin 60-70 72+9 25+5 130+67 640+200 42+19 >0.8 ng/mL >2 ng/mL
Disopyramide 83+11 55+6 30-70 90+50 55+18 7.8+1.6 3+1 lg/mL >8 lg/mL
Erythromycin 18-45 10-15 72+3 420+170 50+14 1.1-3.5
Ethambutol 77+8 79+3 20-30 600+60 110+4 3.1+0.4 >10 lg/mL
Furosemide 40-60 66+7 98.8+0.2 140+30 7.7+1.4 1.5+0.1
Gentamicin >90 <10 90+25 18+6 2-3
Hydralazine 20-60 11-14 87 420-1100 110+21 1.8-3.0 1 lg/mL
Imipramine 47+21 0-2 89-94 1400+1700 1050+420 13+3 >225 ng/mL >1 lg/mL
Indomethacin 98 15+8 90 110+14 65+37 2.6+11.2 0.5-3 lg/mL >6 lg/mL
Lidocaine 35+11 2+1 51+8 640+170 77+28 1.8+0.4 1.2-6 lg/mL >6 lg/mL
Lithium 100 95+15 0 25+8 55+24 22+8 .7-1.5 meq/L 72 meq/L
Meperidine 52+3 4-22 58+9 1200+350 290+90 3.2+0.8
Methotrexate 65 94 45+14 105 28 8.4 0.9 lg/mL
Morphine 20-30 6-10 35+2 1100+40 220+50 3.0+1.2 65 ng/mL
Nortriptyline 51+5 2+1 94.5+0.6 500+130 1300+300 31+13 50-139 ng/mL >500 ng/mL
Phenobarbital >80 24+5 51 6.5+3 62+23 4.4+1.0 days 10-25 lg/mL >30 lg/mL
Phenytoin 98+7 2 89+23 Dose- 45+3 Dose- >10 lg/mL >20 lg/mL
dependent dependent
Prazosin 57+10 <1 93+2 210+20 42+9 2.9+0.8
Procainamide 83+16 67+8 16+5 350-840 130+20 3.0+0.6 3-5 lg/mL >20 lg/mL
Propranolol 36+10 <1 93+1 840+210 270+40 3.9+0.4 20 ng/mL
Quinidine 70+17 18+5 89+1 330+130 190+80 6.2+1.8 2-5 lg/mL >8 lg/mL
Salicylic acid 100 Dose- Dose- Dose- 12+2 Dose- 150-300 lg/mL
dependent dependent dependent dependent
Sulfamethoxazole 100 30+1 62+5 22+3 15+1.4 8.6+0.3
Sulfisoxazole 100 53+9 88-92 23+3.5 10.5+1.4 5.9+0.9
Tetracycline 77 48 65+3 130 91 9.9+1.5
Theophylline 96+8 8 56+4 48+21 35+11 8.1+2.4 10-20 lg/mL >20 lg/mL
Tobramycin 90 <10 77 18+6 2.2+0.1
Tolbutamide 93+10 0 93+1 21+3 11+2 5.9+1.4 80-240 lg/mL
Trimethoprim 100 53+2 70+5 150+40 130+15 11+1.4
Tubocurarine 43+8 40+2 160+50 21+8 2.0+1.1 0.6+0.2 lg/mL
Valproic acid 100 <5 93+4 8.4+2.8 9.1+2.8 16+3 55-100 lg/mL >150 lg/mL
Verapamil 19+12 <3 90+2 830+350 280+60 4.8+2.4 100 ng/mL
Warfarin 100 0 99 3.2+1.7 7.7+0.7 37+15 2.2+0.4 lg/mL

*The values in this table represent the parameters determined when the drug is administered to healthy normal volunteers or to patients who are generally free from
disease except for the condition for which the drug is being prescribed. The values presented here are adapted and updated from Benet LZ,
Sheiner LB: Design and optimization of dosage regimens: Pharmacokinetic data. Pages 1675-1737 in: Goodman and Gilman's The Pharmacological Basis of
Therapeutics 6th ed. Gilman AG, Goodman LS, Gilman A (editors). Macmillan, 1980. This source may be consulted for the effects of disease states on the pertinent
pharmacokinetic parameters.

+No pharmacodynamic values are given for antibiotics since these vary depending upon the infecting organism.
 45

Comparison of First-Order and Non-First-Order Kinetics

 46
Elimination Rate Constant (K) and Elimination Half Live (t1/2)

Assumption: - First-order kinetics

- IV bolus injection
rate of loss ∝ concentration in body (C).
- dC/dt ∝ C
- dC/dt = K.C or dC/dt = K.C

By integration, C = C0 .
e-Kt

Using natural log, InC = InC0 -Kt

or, logC = logC0 - Kt

2.303

Relation between K (β, λη) and t1/2

t1/2 = 0.693 (unit: hr, min)

K

Why:
From: logC = logC0 - Kt
2.303

we have: Kt = logC0 - logC; t = 2.303 logC0

2.303 K C

since: t1/2 is the time when C = 1/2C0

thus, t1/2 = 2.303 log C0 = 2.303 log2 = 2.303 x 0.301 = 0.693/K

K 1/2C0 K K

No matter what kind of model we deal with, this relation between the terminal-phase
elimination t1/2 and the terminal-phase rate of elimination is always true

More about K:

K: elimination rate constant (hr1, min-1)

Values: K3 > K2 > K1

The bigger the values of K, the faster the elimination of the drug.
 47

Practice Problems with solutions

1. Calculation of Vd and ke
Following the administration of 1 gram of a drug to a normal 70 kg volunteer, serial
plasma drug measurements yielded the data shown below.

Figure 11

Which of the following statements is (are) correct?

a. The apparent volume of distribution is about 100 L.

b. The apparent volume of distribution is about 10 L.
c. The rate constant of elimination is about 0.231/hr.
d. The rate constant of elimination is about 0.832/hr.

Solution: Vd = 1000 mg/(10 mg/L) = 100 L

ke = 0.693/t1/2e = 0.693/3 hrs = 0.231/hr
 48

2. Clearance
Morphine has an apparent volume of distribution of 220 L/70 kg and a half-life of
elimination of 3 hours. In a 70 kg man, what is its approximate rate of clearance?

a. 1300 ml/min
b. 850 ml/min
c. 50 ml/min
d. 35 ml/min

Solution: Cl = Vd x ke
Vd = 220L; ke = 0.693/180 minutes = .00385/min
Cl = 220L x .00385/min = 0.847 L/min = 847 ml/min

3. Css with a constant IV infusion

A patient is receiving a constant IV infusion of a drug at a rate of 30 mg/hour. The
elimination half-life of the drug is 4 hours and the volume of distribution is 50L. Which
of the following is(are) correct?

a. After 4 hours, the approximate plasma drug concentration is 1.73 µg/ml.

b. After 8 hours, the approximate plasma drug concentration is 2.60 µg/ml.
c. After 24 hours, the approximate plasma drug concentration is 3.46 µg/ml.
d. After 48 hours, the approximate plasma drug concentration is 30 µg/ml.

Answer : a, b and c are correct.

Solution: Css = ka/(Vd x ke)
ke = 0.693/4 hours = 0.173/hour
Css = (30 mg/hr) / (50 L x 0.173/hr)
= 3.46 mg/L = 3.46 µg/ml

After 4 hours, i.e., one half-life of elimination, we will have achieved 50% of the steady-
state concentration. Thus, at 4 hours, the plasma drug concentration will be 3.46 µg/ml x
0.5, or 1.73 µg/ml; answer a is correct. After 8 hours, i.e., two half-lives of elimination,
we will have achieved 75% of the steady-state concentration. Thus, at 8 hours, the
plasma drug concentration will be 3.46 µg/ml x 0.75. or 2.60 µg/ml; answer b is correct.
After 24 hours, i.e., after more than 4 half-lives of elimination (4 half-lives being the
"rule of thumb" for achievement of the steady-state), we will have achieved the steady-
state concentration of 3.46 µg/ml; answer c is correct. Answer d is wrong because it is
not possible to reach a concentration higher than Css.
 49

4. Css with an oral dosing

A drug has the following properties: Vd = 25 L/70 kg

ke = 0.231/hr
bioavailability = 0.8

If a 70 kg patient took 50 mg of the drug every 8 hours for ten days, what would be the
patient's approximate plasma drug concentration?

a. 0.86 µg/ml
b. 24 µg/ml
c. 10 ng/ml
d. 0.23 µg/ml
e. None of the above

Solution: Css = (1.44 x Dm x F x t1/2e)/(T x Vd)

t1/2 e = 0.693/ke = 0.693/0.231 hr-1 = 3 hours
Css = (1.44 x 50 mg x .8 x 3 hrs)/(8 hrs x 25 L)
= 172.8 mg/200 L = 0.86 mg/L = 0.86 µg/ml

5. Loading Dose
A patient comes into the emergency room with a severe infection and requires immediate
therapy with an antibiotic. The patient weighs 70 kg. The volume of distribution of the
antibiotic is 100 L/70 kg, its bioavailability is 0.5, and the desired steady state
concentration is 10 µg/ml. What would be an appropriate oral loading dose?

a. 1 gram
b. 2 grams
c. 200 mg
d. 800 mg
e. None of the above

Solution: D1 = (Vd x Css)/F = (100,000 ml x 10 µg/ml)/0.5

= 1,000,000 µg/0.5 = 1g/0.5 = 2.0 g
 50

Additional Practice Problems, with solutions appended:

1. The following plasma metoclopramide concentrations were found in a female patient

given a 5 mg IV bolus dose

Figure 12

1.1 What was the order of decay?

1.2 What was the half-life of elimination of metoclopramide in this patient?

1.3 What was the rate constant of elimination?

1.4 What was the apparent volume of distribution of metoclopramide in this patient?

1.5 In another patient, the half-life was 3.1 hours and Vd was 87.6L. Calculate the
total clearance rate in that patient.
 51

2. Procainamide was infused IV into a 60 kg patient for 25 hours at a rate of 2 mg/minute.

The following plasma drug levels were recorded during an after the infusion:

Figure 13

Graph of procainamide concentration against time

2.1 What was the approximate half-life of elimination of the drug in plasma once the
infusion was stopped?

2.2 What was the apparent volume of distribution of procainamide in this patient?
 52

3. An orally active drug has the following properties:

bioavailability = 0.80
Vd = 40L/70 kg
half-time of elimination = 12 hours
half-time of absorption = 1 hour
minimum effective concentration (MEC) = 10 µg/ml
toxic concentration of 25 µg/ml

Which of the following dose schedules would be effective and non-toxic in a 70 kg

patient?

a. 100 mg three times a day

b. 250 mg three times a day
c. 600 mg four times a day
d. 300 mg four times a day

4. During a third year rotation, you are presented a 70 kg female patient who has just
received a renal transplant. The patient is receiving oral cyclosporine, an
immunosuppressive drug which should prevent rejection of her newly transplanted
kidney. For this patient, the drug dose and drug regimen are critical. If the steady-state
concentration (Css) of cyclosporine is less than 100 ng/ml, the patient will likely reject
the transplant; if Css is more than 200 ng/ml. she may suffer serious toxic effects on,
ironically, the kidney.

Although the attending physician has prescribed a dose of 1 gm, to be taken every 24
hours, the tired resident is worried that this dose may be in error. Since you are the one
who has taken pharmacology most recently, you are asked to calculate Css for this dose
regimen. The bioavailability of the drug is 0.5, the apparent volume of distribution is 1.2
L/kg, and the half-life of elimination is 6 hours.

You calculate Css and report that:

a. Css is 150 ng/ml; the dose appears appropriate.
b. Css is 214 ng/ml; the dose is slightly high.
c. Css is 75 ng/ml; good grief, she'll reject her new kidney.
d. Css is 2140 ng/ml; good grief, we're poisoning her new kidney.
 53

5. The same tired resident asks your help with another patient, a 100 kg man with
osteomyelitis who is receiving IV antibiotic therapy. The man has been receiving a
constant IV infusion at a rate of 10 mg/hr for the past 48 hours. The minimal effective
drug concentration is 1.0 µg/ml, while the toxic concentration is 4.0 µg/ml. The apparent
volume of distribution (Vd) is 0.5 L/kg, and the half-life of the drug is 12 hours. A blood
sample obtained last night, 24 hours after the initiation of the infusion, has been found to
have a drug concentration of 2.6 µg/ml. In this case, you calculate that the infusion rate
of 10 mg/hr is delivering a dose which is:

a. too low
b. appropriate
c. slightly high
d. probably lethal

6. A seven year old girl weighing 31 kg appears in the emergency room suffering from
asthma. The decision is made to initiate treatment with the drug theophylline. The
desired steady-state concentration is 15 µg/ml. The apparent volume of distribution (Vd)
for theophylline is 0.5 L/kg, and its oral bioavailability is 0.60. Which of the following
would be the most appropriate intravenous loading dose?

a. 380 mg
b. 232 mg
c. 2.32 gm
d. 3.80 gm
 54

Solution to Problems:

# 1:

1.1 A straight line on semi-log paper indicates first order kinetics.

1.2 The half-life from the graph is approximately 4 hours. The exact answer might
vary as a function of one's artistic skill, but should fall between 3.8 and 4.6 hours.

1.3 ke = 0.693/t1/2e = 0.693/4 hours = 0.17/hour

1.4 Vd = Dose/concentration at t0 = 5mg = 92.5 L

54 ng/ml

1.5 Cl = Vd x ke = 87.6L x (0.693/3.1 hours) = 19.6 L/hour

# 2:

2.1 The half-life of elimination can be determined from the graph, utilizing points
obtained after the infusion was stopped. For example, at 4 hours post-infusion the
concentration was 4 µg/ml, while at 9 hours post-infusion the concentration was 2
µg/ml. Thus, t1/2e is 5 hours.

2.2 With a half-life of about 5 hours, the steady state concentration (Css) had been
approached by 22 hours, at which time the infusion was stopped, i.e., more than 4
half-lives of elimination had transpired. Thus, from the graph, one can assume
that the concentration at the time infusion was stopped, i.e.,7.0 µg/ml, was equal
to Css. Using the IV steady-state equation, the rest is "easy":

Css = ka/(Vd x ke), or

Vd x ke x Css = ka, or
Vd = ka/(ke x Css); ke = 0.693/5 hours = .14 hour
ka = 2 mg/min = 120 mg/hour
= 120,000 µg/hour
Vd = 120,000 µg/hour = 120,000 = 122.4 L
.14/hour x 7 µg/ml 0.98 ml
 55

# 3: b and d are correct

Solution:

a. Css = (1.44 x Dm x F x t1/2e)/(T x Vd)

= (1.44 x 100 mg x 0.80 x 12 hrs)/(8 hrs x 40 L)
= 4.32 µg/ml
(This is less than the MEC and therefore not effective.)

b. Css = 10.80 µg/ml, which is more than the MEC but less than the toxic
concentration.

c. Css = 34.6 µg/ml, which is toxic

d. Css = 17.28 µg/ml, which is also more than the MEC but less than the
toxic concentration.

# 4:

Css = 1.44 x Dm x F x t1/2e = 1.44 x 1000mg x .5 x 6 hrs

T x Vd 24 hrs x 84L
= 4320 mg = 2.14 mg/L = 2.14 µg/ml = 2140 ng/ml
2016 L

# 5:

ke = 0.693/12 hrs = .058/hour

Css = ka/(Vd x ke) = (10 mg/hr)/(50L x .058/hr)
= 3.45 mg/L = 3.45 µg/ml

Note: After 12 hours (i.e., two half-lives, the concentration would be expected to
be 3.45 µg/ml x 0.75, or 2.58 µg/ml.

# 6:

DL = Css x Vd
Vd = 0.5L/kg x 31 kg = 15.5L
DL = 15.0 mg/L x 15.5L
= 232.5 mg
 56

REFERENCES

1. Gibaldi, M. Biopharmaceutics and Clinical Pharmacokinetics. 3rd Edition. Lea &

Febiger, Philadelphia, 1984.

2. Goldstein, A., Aronow, L. and Kalman, S.M. Principles of Drug Action: The Basis of
Pharmacology. Chapters 2 and 3. John Wiley & Sons, New York 1974.

3. Sipes, IG, Gandolfi, AJ: Biotransformation of Toxicants. IN, Toxicology, The Basic
Science of Poisons, Fourth Edition, MO Amdur, J Doull, CD Klaassen, eds., Pergamon
Press, New York, 1991, pp. 88-126.

****************************************************

DRUGS REQUIRED FOR EXAMS

(Within the context of the lectures and syllabus.)

Drug absorption, distribution and elimination

dimethyl sulfoxide (DMSO)

cimetidine
phenobarbital
probenecid
penicillin
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Applied Biopharmaceutics & Pharmacokinetics > Chapter 7. Pharmacokinetics of Oral Absorption >

PHARMACOKINETICS OF DRUG ABSORPTION

The pharmacokinetics of drugs follow ing intravenous drug administration are more simple to model compared to extravascular
delivery (see , , , , , and ). Extravascular delivery routes, particularly oral dosing, are important and popular means of drug
administration. Unlike intravenous administration, in w hich the drug is injected directly into the plasma, pharmacokinetic models
after extravascular drug administration must consider systemic drug absorption from the site of administration, eg, the lung, the
gut, etc., into the plasma. Extravascular drug delivery is further complicated by variables at the absorption site, including possible
drug degradation and significant inter- and intrapatient differences in the rate and extent of absorption. Absorption and
metabolic variables are characterized using pharmacokinetic methods. The variability in systemic drug absorption can be
minimized to some extent by proper biopharmaceutical design of the dosage form to provide predictable and reliable drug
therapy (, , and ). The major advantage of intravenous administration is that the rate and extent of systemic drug input is
carefully controlled.
The systemic drug absorption from the gastrointestinal (GI) tract or from any other extravascular site is dependent on (1) the
physicochemical properties of the drug, (2) the dosage form used, and (3) the anatomy and physiology of the absorption site.
Although this chapter w ill focus primarily on oral dosing, the concepts discussed here may be easily extrapolated to other
extravascular routes. For oral dosing, such factors as surface area of the GI tract, stomach-emptying rate, GI mobility, and blood
flow to the absorption site all affect the rate and the extent of drug absorption. In pharmacokinetics, the overall rate of drug
absorption may be described as either a first-order or zero-order input process. Most pharmacokinetic models assume first-order
absorption unless an assumption of zero-order absorption improves the model significantly or has been verified experimentally.
The rate of change in the amount of drug in the body, dD B/dt, is dependent on the relative rates of drug absorption and
elimination (). The net rate of drug accumulation in the body at any time is equal to the rate of drug absorption less the rate of
drug elimination, regardless of w hether absorption is zero-order or first-order.

Figure 7-1.

Model of drug absorption and elimination.

W here D GI is amount of drug in the gastrointestinal tract and D E is amount of drug eliminated. A plasma level–time curve
show ing drug adsorption and elimination rate processes is given in . During the absorption phase of a plasma level–time curve (),
the rate of drug absorption is greater than the rate of drug elimination. Note that during the absorption phase, elimination
occurs whenever drug is present in the plasma, even though absorption predominates.

Figure 7-2.

117 / 599
Plasma level–time curve for a drug given in a single oral dose. The drug absorption and elimination phases of the curve are shown.

At the peak drug concentration in the plasma () the rate of drug absorption just equals the rate of drug elimination, and there is
no net change in the amount of drug in the body.

Immediately after the time of peak drug absorption, some drug may still be at the absorption site (ie, in the GI tract or other site
of administration). How ever, the rate of drug elimination at this time is faster than the rate of absorption, as represented by the
postabsorption phase in .

W hen the drug at the absorption site becomes depleted, the rate of drug absorption approaches zero, or dD GI /dt = 0. The
plasma level–time curve (now the elimination phase) then represents only the elimination of drug from the body, usually a first-
order process. Therefore, during the elimination phase the rate of change in the amount of drug in the body is described as a
first-order process,

w here k is the first-order elimination rate constant.

ZERO-ORDER ABSORPTION MODEL

Zero-order drug absorption from the dosing site into the plasma usually occurs w hen either the drug is absorbed by a saturable
process or a zero-order controlled-release delivery system is used (see ). The pharmacokinetic model assuming zero-order
absorption is described in . In this model, drug in the gastrointestinal tract, D GI , is absorbed systemically at a constant rate, k 0 .
Drug is simultaneously and immediately eliminated from the body by a first-order rate process defined by a first-order rate
constant, k. This model is analogous to that of the administration of a drug by intravenous infusion ().

Figure 7-3.

One-compartment pharmacokinetic model for zero-order drug absorption and first-order drug elimination.

The rate of first-order elimination at any time is equal to D Bk. The rate of input is simply k 0 . Therefore, the net change per unit
time in the body can be expressed as
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Integration of this equation w ith substitution of V D C p for D B produces

The rate of drug absorption is constant until the amount of drug in the gut, D GI , is depleted. The time for complete drug
absorption to occur is equal to D GI /k 0 . After this time, the drug is no longer available for absorption from the gut, and Equation
7.7 no longer holds. The drug concentration in the plasma subsequently declines in accordance w ith a first-order elimination rate
process.

FIRST-ORDER ABSORPTION MODEL

Although zero-order absorption can occur, absorption is usually assumed to be a first-order process. This model assumes a first-
order input across the gut w all and first-order elimination from the body (). This model applies mostly to the oral absorption of
drugs in solution or rapidly dissolving dosage (immediate release) forms such as tablets, capsules, and suppositories. In
addition, drugs given by intramuscular or subcutaneous aqueous injections may also be described using a first-order process.

Figure 7-4.

One-compartment pharmacokinetic model for first-order drug absorption and first-order elimination.

In the case of a drug given orally, the dosage form first disintegrates if it is given as a solid, then the drug dissolves into the
fluids of the GI tract. Only drug in solution is absorbed into the body. The rate of disappearance of drug from the gastrointestinal
tract is described by

w here k a is the first-order absorption rate constant from the GI tract, F is the fraction absorbed, and D GI is the amount of drug
in solution in the GI tract at any time t. Integration of the differential equation (7.8) gives

w here D 0 is the dose of the drug.

The rate of drug elimination is described by a first-order rate process for most drugs and is equal to –kD B. The rate of drug
change in the body, dD B/dt, is therefore the rate of drug in, minus the rate of drug out—as given by the differential equation,
Equation 7.10:

w here F is the fraction of drug absorbed systemically. Since the drug in the gastrointestinal tract also follow s a first-order decline
(ie, the drug is absorbed across the gastrointestinal w all), the amount of drug in the gastrointestinal tract at any time t is equal
to D 0 e –k at .

The value of F may vary from 1 for a fully absorbed drug to 0 for a drug that is completely unabsorbed. This equation can be
integrated to give the general oral absorption equation for calculation of the drug concentration (C p ) in the plasma at any time t,
as show n below .

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A typical plot of the concentration of drug in the body after a single oral dose is presented in .

Figure 7-5.

Typical plasma level–time curve for a drug given in a single oral close.

The maximum plasma concentration after oral dosing is C m ax , and the time needed to reach maximum concentration is t m ax .
The t m ax is independent of dose and is dependent on the rate constants for absorption (k a ) and elimination (k) (Eq. 7.13a). At
C m ax , sometimes called peak concentration, the rate of drug absorbed is equal to the rate of drug eliminated. Therefore, the net
rate of concentration change is equal to zero. At C m ax , the rate of concentration change can be obtained by differentiating
Equation 7.12, as follow s:

This can be simplified as follow s:

As show n in Equation 7.13a, the time for maximum drug concentration, t m ax , is dependent only on the rate constants k a and k.
In order to calculate C m ax , the value for t m ax is determined via Equation 7.13a and then substituted into Equation 7.11, solving
for C m ax . Equation 7.11 show s that C m ax is directly proportional to the dose of drug given (D 0 ) and the fraction of drug
absorbed (F). Calculation of t m ax and C m ax is usually necessary, since direct measurement of the maximum drug concentration
may not be possible due to improper timing of the serum samples.
The first-order elimination rate constant may be determined from the elimination phase of the plasma level–time curve (). At later
time intervals, w hen drug absorption has been completed, ie, e –k at ≈ 0, Equation 7.11 reduces to

Taking the natural logarithm of this expression,

Substitution of common logarithms gives

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W ith this equation, a graph constructed by plotting log C p versus time w ill yield a straight line w ith a slope of –k/2.3 ().

Figure 7-6.

A. Plasma drug concentration versus time, single oral dose. B. Rate of urinary drug excretion versus time, single oral dose.

W ith a similar approach, urinary drug excretion data may also be used for calculation of the first-order elimination rate constant.
The rate of drug excretion after a single oral dose of drug is given by

w here dD u /dt = rate of urinary drug excretion, k e = first-order renal excretion constant, and F = fraction of dose absorbed.

A graph constructed by plotting dD u /dt versus time w ill yield a curve identical in appearance to the plasma level–time curve for
the drug (). After drug absorption is virtually complete, –e–kat approaches zero, and Equation 7.17 reduces to

Figure 7-7.

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A. Plasma drug concentration versus time, single oral dose. B. Rate of urinary drug excretion versus time, single oral dose.

Taking the natural logarithm of both sides of this expression and substituting for common logarithms, Equation 7.18 becomes

W hen log (dD u /dt) is plotted against time, a graph of a straight line is obtained w ith a slope of –k/2.3 (). Because the rate of
urinary drug excretion, dD u /dt, cannot be determined directly for any given time point, an average rate of urinary drug excretion
is obtained (see also ), and this value is plotted against the midpoint of the collection period for each urine sample.
To obtain the cumulative drug excretion in the urine, Equation 7.17 must be integrated, as show n below .

A plot of D u versus time w ill give the urinary drug excretion curve described in . W hen all of the drug has been excreted, at t =
∞. Equation 7.20 reduces to

w here D ∞ u is the maximum amount of active or parent drug excreted.

Figure 7-8.

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C umulative urinary drug excretion versus time, single oral dose. Urine samples are collected at various time periods after the dose. The
amount of drug excreted in each sample is added to the amount of drug recovered in the previous urine sample (cumulative addition). The
total amount of drug recovered after all the drug is excreted is D ∞ u.

Determination of Absorption Rate Constants from Oral Absorption Data

MET HOD OF RESIDUALS
Assuming k a >> k in Equation 7.11, the value for the second exponential w ill become insignificantly small w ith time (ie, e –k at ≈
0) and can therefore be omitted. W hen this is the case, drug absorption is virtually complete. Equation 7.11 then reduces to
Equation 7.22.

From this, one may also obtain the intercept of the y axis ().

w here A is a constant. Thus, Equation 7.22 becomes

This equation, w hich represents first-order drug elimination, w ill yield a linear plot on semilog paper. The slope is equal to –k/2.3.
The value for k a can be obtained by using the method of residuals or a feathering technique, as described in . The value of k a is
obtained by the follow ing procedure:
1. Plot the drug concentration versus time on semilog paper w ith the concentration values on the logarithmic axis ().
2. Obtain the slope of the terminal phase (line BC, ) by extrapolation.
3. Take any points on the upper part of line BC (eg, x'1 , x'2 , x'3 , . . .) and drop vertically to obtain corresponding points on the
curve (eg, x 1 , x 2 , x 3 , . . .).

4. Read the concentration values at x 1 and x'1 , x 2 and x'2 , x 3 and x'3 , and so on. Plot the values of the differences at the
corresponding time points 1 , 2 , 3 , . . . . A straight line w ill be obtained w ith a slope of –k a /2.3 ().

Figure 7-9.

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Plasma level–time curve for a drug demonstrating first-order absorption and elimination kinetics. The equation of the curve is obtained by
the method of residuals.

W hen using the method of residuals, a minimum of three points should be used to define the straight line. Data points occurring
shortly after t m ax may not be accurate, because drug absorption is still continuing at that time. Because this portion of the curve
represents the postabsorption phase, only data points from the elimination phase should be used to define the rate of drug
absorption as a first-order process.
If drug absorption begins immediately after oral administration, the residual lines obtained by feathering the plasma level–time
curve (as show n in ) w ill intersect on the y axis at point A. The value of this y intercept, A, represents a hybrid constant
composed of k a , k, V D , and FD 0 . The value of A has no direct physiologic meaning (see Eq. 7.23).

The value for A, as w ell as the values for k and k a , may be substituted back into Equation 7.11 to obtain a general theoretical
equation that w ill describe the plasma level–time curve.

LAG T IME
In some individuals, absorption of drug after a single oral dose does not start immediately, due to such physiologic factors as
stomach-emptying time and intestinal motility. The time delay prior to the commencement of first-order drug absorption is know n
as lag time.
The lag time for a drug may be observed if the tw o residual lines obtained by feathering the oral absorption plasma level–time
curve intersect at a point greater than t = 0 on the x axis. The time at the point of intersection on the x axis is the lag time ().

Figure 7-10.

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The lag time can be determined graphically if the two residual lines obtained by feathering the plasma level–time curve intersect at a point
where t > 0.

The lag time, t 0 , represents the beginning of drug absorption and should not be confused w ith the pharmacologic term onset
time, w hich represents latency, eg, the time required for the drug to reach minimum effective concentration.
Tw o equations can adequately describe the curve in . In one, the lag time t 0 is subtracted from each time point, as show n in
Equation 7.24.

w here Fk a D 0 /V D (k a –k) is the y value at the point of intersection of the residual lines in .

The second expression that describes the curve in omits the lag time, as follow s:

w here A and B represents the intercepts on the y axis after extrapolation of the residual lines for absorption and elimination,
respectively.

FLIP-FLOP OF K A AND K
In using the method of residuals to obtain estimates of k a and k, the terminal phase of an oral absorption curve is usually
represented by k w hereas the steeper slope is represented by k a (). In a few cases, the elimination rate constant k obtained
from oral absorption data does not agree w ith that obtained after intravenous bolus injection. For example, the k obtained after
an intravenous bolus injection of a bronchodilator w as 1.72 hr– 1 , w hereas the k calculated after oral administration w as 0.7 hr–
1 (). W hen k w as obtained by the method of residuals, the rather surprising result w as that the k w as 1.72 hr– 1 .
a a

Figure 7-11.

Flip-flop of k a and k. Because k > k a, the right-hand figure and slopes represent the correct values for k a and k.

Apparently, the k a and k obtained by the method of residuals has been interchanged. This phenomenon is called flip-flop of the
absorption and elimination rate constants. Flip-flop, or the reversal of the rate constants, may occur w henever k a and k are
estimated from oral drug absorption data. Use of computer methods does not ensure against flip-flop of the tw o constants
estimated.
In order to demonstrate unambiguously that the steeper curve represents the elimination rate for a drug given extravascularly,
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In order to demonstrate unambiguously that the steeper curve represents the elimination rate for a drug given extravascularly,
the drug must be given by intravenous injection into the same patient. After intravenous injection, the decline in plasma drug
levels over time represents the true elimination rate. The relationship betw een k a and k on the shape of the plasma drug
concentration–time curve for a constant dose of drug given orally is show n in .
Most of the drugs observed to have flip-flop characteristics are drugs w ith fast elimination (ie, k > k a ). Drug absorption of most
drug solutions or fast-dissolving products are essentially complete or at least half-complete w ithin an hour (ie, absorption half-
life of 0.5 or 1 hr, corresponding to a k a of 1.38 hr– 1 or 0.69 hr– 1 ). Because most of the drugs used orally have longer
elimination half-lives compared to absorption half-lives, the assumption that the smaller slope or smaller rate constant (ie, the
terminal phase of the curve in ) should be used as the elimination constant is generally correct.

For drugs that have a large elimination rate constant (k > 0.69 hr– 1 ), the chance for flip-flop of k a and k is much greater. The
drug isoproterenol, for example, has an oral elimination half-life of only a few minutes, and flip-flop of k a and k has been noted
(). Similarly, salicyluric acid w as flip-flopped w hen oral data w ere plotted. The k for salicyluric acid w as much larger than its k a ().
Many experimental drugs show flip-flop of k and k a , w hereas few marketed oral drugs do. Drugs w ith a large k are usually
considered to be unsuitable for an oral drug product due to their large elimination rate constant, corresponding to a very short
elimination half-life. An extended-release drug product may slow the absorption of a drug, such that the k a is smaller than the k
and producing a flip-flop situation.

DET ERMINAT ION OF K A BY PLOT T ING PERCENT OF DRUG UNABSORBED VERSUS T IME
(WAGNER–NELSON MET HOD)
After a single oral dose of a drug, the total dose should be completely accounted for in the amount present in the body, the
amount present in the urine, and the amount present in the GI tract. Therefore, dose (D 0 ) is expressed as follow s:

Let Ab = D B + D u = amount of drug absorbed and let Ab ∞ = amount of drug absorbed at t = ∞. At any given time the fraction of
drug absorbed is Ab/Ab ∞, and the fraction of drug unabsorbed is 1 – (Ab/Ab ∞). The amount of drug excreted at any time t can be
calculated as

The amount of drug in the body (D B), at any time, = C p V D . At any time t, the amount of drug absorbed (Ab) is

At t = ∞, C ∞ p = 0 (ie, plasma concentration is negligible), and the total amount of drug absorbed is

The fraction of drug absorbed at any time is

The fraction unabsorbed at any time t is

The drug remaining in the GI tract at any time t is

Therefore, the fraction of drug remaining is

Because D GI /D 0 is actually the fraction of drug unabsorbed—that is, 1 – (Ab/Ab ∞)—a plot of 1 – (Ab/Ab ∞) versus time gives –k
a /2.3 as the slope ().

Figure 7-12.

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Semilog graph of data in , depicting the fraction of drug unabsorbed versus time using the Wagner–Nelson method.

The follow ing steps should be useful in determination of k a :

1. Plot log concentration of drug versus time.

2. Find k from the terminal part of the slope w hen the slope = –k/2.3.

3. Find [AUC]t 0 by plotting C p versus t.

4. Find k[AUC]t 0 by multiplying each [AUC]t 0 by k.

5. Find [AUC]∞ 0 by adding up all the [AUC] pieces, from t = 0 to t = ∞

6. Determine the 1 – (Ab/Ab ∞) value corresponding to each time point t by using .

7. Plot 1 – (Ab/Ab ∞) versus time on semilog paper, w ith 1 – (Ab/Ab ∞) on the logarithmic axis.

Table 7.1 Blood Concentrations and Associated Data for a Hypothetical Drug

Time tn (hr) Concentration C P ( g/mL) [AUC]t n t t t

t n–1 [AUC] 0 k[AUC] 0 C p + k[AUC] 0

0 0. 0. 0. 1.000
1 3.13 1.57 1.57 0.157 3.287 0.328 0.672
2 4.93 4.03 5.60 0.560 5.490 0.548 0.452
3 5.86 5.40 10.99 1.099 6.959 0.695 0.305
4 6.25 6.06 17.05 1.705 7.955 0.794 0.205
5 6.28 6.26 23.31 2.331 8.610 0.856 0.140
6 6.11 6.20 29.51 2.951 9.061 0.905 0.095
7 5.81 5.96 35.47 3.547 9.357 0.934 0.066
8 5.45 5.63 41.10 4.110 9.560 0.955 0.045
9 5.06 5.26 46.35 4.635 9.695 0.968 0.032
10 4.66 4.86 51.21 5.121
12 3.90 8.56 59.77 5.977
14 3.24 7.14 66.91 6.691
16 2.67 5.92 72.83 7.283
18 2.19 4.86 77.69 7.769
24 1.20 10.17 87.85 8.785
28 0.81 4.02 91.87 9.187
32 0.54 2.70 94.57 9.457
36 0.36 1.80 96.37 9.637
48 0.10 2.76 99.13 9.913

k = 0.1 hr– 1

If the fraction of drug unabsorbed, 1 – Ab/Ab ∞, gives a linear regression line on a semilog graph, then the rate of drug
absorption, dD GI /dt, is a first-order process. Recall that 1 – Ab/Ab ∞ is equal to dD GI /dt ().

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As the drug approaches 100% absorption, C p becomes very small and difficult to assay accurately. Consequently, the terminal
part of the line described by 1 – Ab/Ab ∞ versus time tends to become scattered or nonlinear. This terminal part of the curve is
excluded, and only the initial linear segment of the curve is used for the estimate of the slope.

PRACT ICE PROBLEM

Drug concentrations in the blood at various times are listed in . Assuming the drug follow s a one-compartment model, find the k
a , and compare it w ith the k a value obtained by the method of residuals.

Solution
The AUC is approximated by the trapezoidal rule. This method is fairly accurate w hen there are sufficient data points. The area
betw een each time point is calculated as

w here C n and C n – 1 are concentrations. For example, at n = 6, the [AUC] is

To obtain [AUC]∞ 0 , add all the area portions under the curve from zero to infinity. In this case, 48 hours is long enough to be
considered as infinity, because the blood concentration at that point already has fallen to an insignificant drug concentration, 0.1
g/mL. The rest of the needed information is given in . Notice that k is obtained from the plot of log C p versus t; k w as found to
be 0.1 hr– 1 . The plot of 1–(Ab/Ab ∞) versus t on semilog paper is show n in .
A more complete method of obtaining the is to estimate the residual area from the last observed plasma concentration, C p n at t

n to time equal to infinity. This equation is

The total [AUC]∞ 0 is the sum of the areas obtained by the trapezoidal rule, [AUC]∞ 0 , and the residual area [AUC]∞ t , as
described in the follow ing expression:

EST IMAT ION OF K A FROM URINARY DAT A

The absorption rate constant may also be estimated from urinary excretion data, using a plot of percent of drug unabsorbed
versus time. For a one-compartment model:

The differential of Equation 7.38 w ith respect to time gives

Assuming first-order elimination kinetics w ith renal elimination constant k e ,

Assuming a one-compartment model,

Substituting V D C p into Equation 7.39,

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And rearranging Equation 7.40,

Substituting for dC p /dt into Equation 7.41 and kD u /k e for D E,

W hen the above expression is integrated from zero to time t,

At t = ∞ all the drug that is ultimately absorbed is expressed as Ab ∞ and dD u /dt = 0. The total amount of drug absorbed is

w here D ∞ u is the total amount of unchanged drug excreted in the urine.

The fraction of drug absorbed at any time t is equal to the amount of drug absorbed at this time, Ab t, divided by the total amount
of drug absorbed, Ab ∞.

A plot of the fraction of drug unabsorbed, 1 – Ab/Ab ∞, versus time gives –k a /2.3 as the slope from w hich the absorption rate
constant is obtained (; refer to Eq. 7-34).
W hen collecting urinary drug samples for the determination of pharmacokinetic parameters, one should obtain a valid urine
collection as discussed in . If the drug is rapidly absorbed, it may be difficult to obtain multiple early urine samples to describe the
absorption phase accurately. Moreover, drugs w ith very slow absorption w ill have low concentrations, w hich may present
analytical problems.

EFFECT OF K A AND K ON C MAX, T MAX, AND AUC

Changes in k a and k may affect t m ax , C m ax , and AUC as show n in . If the values for k a and k are reversed, then the same t
– 1 and the k changes
m ax is obtained, but the C m ax and AUC are different. If the elimination rate constant is kept at 0.1 hr a

from 0.2 to 0.6 hr– 1 (absorption rate increases), then the t m ax becomes shorter (from 6.93 to 3.58 hr), the C m ax increases
(from 5.00 to 6.99 g/mL), but the AUC remains constant (100 g hr/mL). In contrast, w hen the absorption rate constant is kept
at 0.3 hr– 1 and k changes from 0.1 to 0.5 hr– 1 (elimination rate increases), then the t m ax decreases (from 5.49 to 2.55 hr), the
C m ax decreases (from 5.77 to 2.79 g/mL), and the AUC decreases (from 100 to 20 g hr/mL). Graphical representations for the
relationships of k a and k on the time for peak absorption and the peak drug concentrations are show n in and .

Table 7.2 Effects of the Absorption Rate Constant and Elimination Ratea

Absorption Rate Constant k a (hr–1) Elimination Rate Constant k (hr–1) t max (hr) C max ( g/mL) AUC ( g hr/mL)

0.1 0.2 6.93 2.50 50

0.2 0.1 6.93 5.00 100
0.3 0.1 5.49 5.77 100
0.4 0.1 4.62 6.29 100
0.5 0.1 4.02 6.69 100
0.6 0.1 3.58 6.99 100
0.3 0.1 5.49 5.77 100
0.3 0.2 4.05 4.44 50
0.3 0.3 3.33 3.68 33.3
0.3 0.4 2.88 3.16 25
0.3 0.5 2.55 2.79 20
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a t
m ax = peak plasma concentration, C m ax = peak drug concentration, AUC = area under the curve. Values are based on a
single oral dose (100 mg) that is 100% bioavailable (F = 1) and has an apparent V D of 10 L. The drug follow s a one-
compartment open model. t m ax is calculated by Eq. 7.13 and C m ax is calculated by Eq. 7.11. The AUC is calculated by the
trapezoidal rule from 0 to 24 hours.

Figure 7-13.

Effect of a change in the absorption rate constant, k a, on the plasma drug concentration-versus-time curve. Dose of drug is 100 mg, V D is
10 L, and k is 0.1 hr – 1 .

Figure 7-14.

Effect of a change in the elimination rate constant, k, on the plasma drug concentration-versus-time curve. Dose of drug is 100 mg, V D is
10 L, and k a is 0.1 hr – 1 .

DET ERMINAT ION OF K A FROM T WO-COMPART MENT ORAL ABSORPT ION DAT A (LOO
–RIEGELMAN MET HOD)
Plotting the percent of drug unabsorbed versus time to determine the k a may be calculated for a drug exhibiting a tw o-
compartment kinetic model. As in the method used previously to obtain an estimate of the k a , no limitation is placed on the
order of the absorption process. How ever, this method does require that the drug be given intravenously as w ell as orally to
obtain all the necessary kinetic constants.
After oral administration of a dose of a drug that exhibits tw o-compartment model kinetics, the amount of drug absorbed is
calculated as the sum of the amounts of drug in the central compartment (D p ) and in the tissue compartment (D t) and the
amount of drug eliminated by all routes (D u ) ().
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amount of drug eliminated by all routes (D u ) ().

Figure 7-15.

Two-compartment pharmacokinetic mode. Drug absorption and elimination occur from the central compartment.

Each of these terms may be expressed in terms of kinetics constants and plasma drug concentrations, as follow s:

Substituting the above expression for D p and D u into Equation 7.46,

By dividing this equation by V p to express the equation on drug concentrations, w e obtain

At t = ∞ this equation becomes

Equation 7.53 divided by Equation 7.54 gives the fraction of drug absorbed at any time.

A plot of the fraction of drug unabsorbed, 1 – Ab/Ab ∞, versus time gives –k a /2.3 as the slope from w hich the value for the
absorption rate constant is obtained (refer to Eq. 7-34).

C p and k [AUC]t 0 are calculated from a plot of C p versus time. Values for (D t/V p ) can be approximated by the Loo–Riegelman
method, as follow s:

w here C t is D t/V p , or apparent tissue concentration; t = time of sampling for sample n; t n –1 = time of sampling for the
sampling point preceding sample n; and (C p )t n–1 = concentration of drug at central compartment for sample n – 1.

Calculation of C t values is show n in , using a typical set of oral absorption data. After calculation of C t values, the percent of
drug unabsorbed is calculated w ith Equation 7.54, as show n in . A plot of percent of drug unabsorbed versus time on semilog
graph paper gives a k a of approximately 0.5 hr– 1 .

Table 7.3 Calculation of C t Valuesa

(C (t) t n Cp t (C p) t (k 12/k 21) x (1 – e–k (C p) t n–1 k 12/k 21 x (1 – e–k (C t ) t n–1 e–k (C t

p) t n n–1 t) )tn
21 21 t) 21 t
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p) t n n–1 t) )tn
21 21 t) 21 t

3.00 0.5 3.0 0.5 0.218 0 0.134 0 0 0.218

5.20 1.0 2.2 0.5 0.160 3.00 0.134 0.402 0.187 0.749
6.50 1.5 1.3 0.5 0.094 5.20 0.134 0.697 0.642 1.433
7.30 2.0 0.8 0.5 0.058 6.50 0.134 0.871 1.228 2.157
7.60 2.5 0.3 0.5 0.022 7.30 0.134 0.978 1.849 2.849
7.75 3.0 0.15 0.5 0.011 7.60 0.134 1.018 2.442 3.471
7.70 3.5 –0.05 0.5 –0.004 7.75 0.134 1.039 2.976 4.019
7.60 4.0 –0.10 0.5 –0.007 7.70 0.134 1.032 3.444 4.469
7.10 5.0 –0.50 1.0 –0.073 7.60 0.250 1.900 3.276 5.103
6.60 6.0 –0.50 1.0 –0.073 7.10 0.250 1.775 3.740 5.442
6.00 7.0 –0.60 1.0 –0.087 6.60 0.250 1.650 3.989 5.552
5.10 9.0 –0.90 2.0 –2.261 6.00 0.432 2.592 2.987 5.318
4.40 11.0 –0.70 2.0 –0.203 5.10 0.432 2.203 2.861 4.861
3.30 15.0 –1.10 4.0 –0.638 4.40 0.720 3.168 1.361 3.891

aC alculated with the following rate constants: k – 1, k – 1.

12 = 0.29 hr 21 = 0.31

Adapted with permission from .

Table 7.4 Calculation of Percentage Unabsorbeda

Time (hr) (C p) t n [AUC]t n t t (C t ) t n Ab/V p %Ab/V p 100% – Ab/V p%

t n–1 [AUC] n t 0 k[AUC] n t 0

0.5 3.00 0.750 0.750 0.120 0.218 3.338 16.6 83.4

1.0 5.20 2.050 2.800 0.448 0.749 6.397 31.8 68.2
1.5 6.50 2.925 5.725 0.916 1.433 8.849 44.0 56.0
2.0 7.30 3.450 9.175 1.468 2.157 10.925 54.3 45.7
2.5 7.60 3.725 12.900 2.064 2.849 12.513 62.2 37.8
3.0 7.75 3.838 16.738 2.678 3.471 13.889 69.1 30.9
3.5 7.70 3.863 20.601 3.296 4.019 15.015 74.6 25.4
4.0 7.60 3.825 24.426 3.908 4.469 15.977 79.4 20.6
5.0 7.10 7.350 31.726 5.084 5.103 17.287 85.9 14.1
6.0 6.60 6.850 38.626 6.180 5.442 18.222 90.6 9.4
7.0 6.00 6.300 44.926 7.188 5.552 18.740 93.1 6.9
9.0 5.10 11.100 56.026 8.964 5.318 19.382 96.3 3.7
11.0 4.40 9.500 65.526 10.484 4.861 19.745 98.1 1.9
15.0 3.30 15.400 80.926 12.948 3.891 20.139 100.0 0

For calculation of the k a by this method, the drug must be given intravenously to allow evaluation of the distribution and
elimination rate constants. For drugs that cannot be given by the IV route, the k a cannot be calculated by the Loo–Riegelman
method. For these drugs, given by the oral route only, the Wagner–Nelson method, w hich assumes a one-compartment model,
may be used to provide an initial estimate of k a . If the drug is given intravenously, there is no w ay of know ing w hether there is
any variation in the values for the elimination rate constant k and the distributive rate constants k 12 and k 21 . Such variations
alter the rate constants. Therefore, a one-compartment model is frequently used to fit the plasma curves after an oral or
intramuscular dose. The plasma level predicted from the k a obtained by this method does deviate from the actual plasma level.
How ever, in many instances, this deviation is not significant.

CUMULAT IVE RELAT IVE FRACT ION ABSORBED

The fraction of drug absorbed at any time t (Eq. 7.31) may be summed or cumulated for each time period for w hich a plasma drug
sample w as obtained. From Equation 7.31, the term Ab/Ab ∞ becomes the cumulative relative fraction absorbed (CRFA).

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w here C p t is the plasma concentration at time t.

In the Wagner–Nelson equation, Ab/Ab ∞ or CRFA w ill eventually equal unity, or 100%, even though the drug may not be 100%
systemically bioavailable. The percent of drug absorbed is based on the total amount of drug absorbed (Ab ∞) rather than the
dose D 0 . Because the amount of the drug ultimately absorbed, Ab ∞, is equal to k[AUC]∞ 0 , the numerator w ill alw ays equal the
denominator, w hether the drug is 10, 20, or 100% bioavailable. The percent of drug absorbed based on Ab/Ab ∞ is therefore
different from the real percent of drug absorbed unless F = 1. How ever, for the calculation of k a , the method is acceptable.

To determine the real percent of drug absorbed, a modification of the Wagner–Nelson equation w as suggested by . A reference
drug product w as administered and plasma drug concentrations w ere determined over time. CRFA w as then estimated by
dividing Ab/Ab ∞ ref , w here Ab is the cumulative amount of drug absorbed from the drug product and Ab ∞ ref is the cumulative
final amount of drug absorbed from a reference dosage form. In this case, the denominator of Equation 7.56 is modified as
follow s:

w here k ref and [AUC]∞ ref are the elimination constant and the area under the curve determined from the reference product.
The terms in the numerator of Equation 7.57 refer to the product, as in Equation 7.56.
Each fraction of drug absorbed is cumulated and plotted against the time interval in w hich the plasma drug sample w as obtained
(). An example of the relationship of CRFA versus time for the absorption of tolazamide from four different drug products is show n
in . The data for w ere obtained from the serum tolazamide levels–time curves in . The CRFA–time graph provides a visual image
of the relative rates of drug absorption from various drug products. If the CRFA–time curve is a straight line, then the drug w as
absorbed from the drug product at an apparent zero-order absorption rate.

Figure 7-16.

Fraction of drug absorbed. (Wagner–Nelson method).

Figure 7-17.

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Mean cumulative relative fractions of tolazamide absorbed as a function of time.
()

Figure 7-18.

Mean serum tolazamide levels as a function of time.

()

SIGNIFICANCE OF ABSORPTION RATE CONSTANTS

The overall rate of systemic drug absorption from an orally administered solid dosage form encompasses many individual rate
processes, including dissolution of the drug, GI motility, blood flow , and transport of the drug across the capillary membranes and
into the systemic circulation. The rate of drug absorption represents the net result of all these processes. The selection of a
model w ith either first-order or zero-order absorption is generally empirical.
The actual drug absorption process may be zero-order, first-order, or a combination of rate processes that is not easily
quantitated. For many immediate-release dosage forms, the absorption process is first-order due to the physical nature of drug
diffusion. For certain controlled-release drug products, the rate of drug absorption may be more appropriately described by a
zero-order rate constant.
The calculation of k a is useful in designing a multiple-dosage regimen. Know ledge of the k a and k allow s for the prediction of
peak and trough plasma drug concentrations follow ing multiple dosing. In bioequivalence studies, drug products are given in
chemically equivalent (ie, pharmaceutical equivalents) doses, and the respective rates of systemic absorption may not differ
markedly. Therefore, for these studies, t m ax , or time of peak drug concentration, can be very useful in comparing the respective
rates of absorption of a drug from chemically equivalent drug products.

FREQUENTLY ASKED QUESTIONS

1. W hat is the absorption half-life of a drug and how is it determined?
2. W hen one simulates drug absorption w ith the oral one-compartment model, w ould a greater absorption rate constant
result in a greater amount of drug absorbed?
3. How do you explain that k a is often greater than k w ith most drugs?

4. Drug clearance is dependent on dose and area under the time–drug concentration curve. Would drug clearance be affected
by the rate of absorption?
5. In sw itching a drug from IV to oral dosing, w hat is the most important consideration?

LEARNING QUESTIONS
1. Plasma samples from a patient w ere collected after an oral bolus dose of 10 mg of a new benzodiazepine solution as follow s:

Time (hr) Concentration (ng/mL)

0.25 2.85
0.50 5.43
0.75 7.75
1.00 9.84
2.00 16.20
4.00 22.15
6.00 23.01
10.00 19.09
14.00 13.90
20.00 7.97
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 From the data above:
a. Determine the elimination constant of the drug.
b. Determine k a by feathering.

c. Determine the equation that describes the plasma drug concentration of the new benzodiazepine.
2. Assuming that the drug in Question 1 is 80% absorbed, find (a) the absorption constant, k a ; (b) the elimination half-life, t
1/2 ; (c) the t m ax , or time of peak drug concentration; and (d) the volume of distribution of the patient.

3. Contrast the percent of drug-unabsorbed methods for the determination of rate constant for absorption, k a , in terms of (a)
pharmacokinetic model, (b) route of drug administration, and (c) possible sources of error.
4. W hat is the error inherent in the measurement of k a for an orally administered drug that follow s a tw o-compartment model
w hen a one-compartment model is assumed in the calculation?
5. W hat are the main pharmacokinetic parameters that influence (a) time for peak drug concentration and (b) peak drug
concentration?
6. Name a method of drug administration that w ill provide a zero-order input.
7. A single oral dose (100 mg) of an antibiotic w as given to an adult male patient (43 years, 72 kg). From the literature, the
pharmacokinetics of this drug fit a one-compartment open model. The equation that best fits the pharmacokinetics of the drug is

From the equation above, calculate (a)t m ax , (b)C m ax , and (c)t 1/2 for the drug in this patient. Assume C p is in g/mL and the
first-order rate constants are in hours – 1 .
8. Tw o drugs, A and B, have the follow ing pharmacokinetic parameters after a single oral dose of 500 mg:

Drug k (hr– 1) k (hr– 1) V D (mL)

a

A 1.0 0.2 10,000

B 0.2 1.0 20,000

Both drugs follow a one-compartment pharmacokinetic model and are 100% bioavailable.
a. Calculate the t m ax for each drug.

b. Calculate the C m ax for each drug.

9. The bioavailability of phenylpropanolamine hydrochloride w as studied in 24 adult male subjects. The follow ing data represent
the mean blood phenylpropanolamine hydrochloride concentrations (ng/mL) after the oral administration of a single 25-mg dose
of phenylpropanolamine hydrochloride solution.

Time (hr) Concentration (ng/mL) Time (hr) Concentration (ng/mL)

0 0 3 62.98
0.25 51.33 4 52.32
0.5 74.05 6 36.08
0.75 82.91 8 24.88
1.0 85.11 12 11.83
1.5 81.76 18 3.88
2 75.51 24 1.27

a. From the data, obtain the rate constant for absorption, k a , and the rate constant for elimination, k, by the method of
residuals.
b. Is it reasonable to assume that k a > k for a drug in a solution? How w ould you determine unequivocally w hich rate
constant represents the elimination constant k?
c. From the data, w hich method, Wagner–Nelson or Loo–Riegelman, w ould be more appropriate to determine the order of the
rate constant for absorption?
d. From your values, calculate the theoretical t m ax . How does your value relate to the observed t m ax obtained from the
subjects?
e. Would you consider the pharmacokinetics of phenylpropanolamine HCl to follow a one-compartment model? W hy?

REFERENCES
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Levy G, Amsel LP, Elliot HC: Kinetics of salicyluric acid elimination in man. J Pharm Sci 58:827–829, 1969 [PMID: 5810199]

Loo JCK, Riegelman S: New method for calculating the intrinsic absorption rate of drugs. J Pharm Sci 57:918–928, 1968 [PMID:
5671338]

Portmann G: Pharmacokinetics. In Sw arbrick J (ed), Current Concepts in the Pharmaceutical Sciences, vol 1. Philadelphia, Lea &
Febiger, 1970, Chap 1

Welling PG: Pharmacokinetics: Processes and Mathematics. ACS monograph 185. Washington, DC, American Chemical Society,
1986, pp 174–175

Welling PG, Patel RB, Patel UR, et al: Bioavailability of tolazamide from tablets: Comparison of in vitro and in vivo results. J Pharm
Sci 71:1259, 1982 [PMID: 7175719]

Wagner JG: Use of computers in pharmacokinetics. Clin Pharmacol Ther 8:201–218, 1967 [PMID: 6015601]

BIBLIOGRAPHY
Boxenbaum HG, Kaplan SA: Potential source of error in absorption rate calculations. J Pharmacokinet Biopharm 3:257–264, 1975
[PMID: 1185523]

Boyes R, Adams H, Duce B: Oral absorption and disposition kinetics of lidocaine hydrochloride in dogs. J Pharmacol Exp Ther 174:1
–8, 1970 [PMID: 5424701]

Dvorchik BH, Vesell ES: Significance of error associated w ith use of the one-compartment formula to calculate clearance of 38
drugs. Clin Pharmacol Ther 23:617–623, 1978 [PMID: 648075]

Wagner JG, Nelson E: Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J
Pharm Sci 53:1392, 1964 [PMID: 14253604]

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