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General Principles of Drug Therapy

Integrated Scientific and
Clinical Pharmacology

Pharmacokinetics I:
ADME
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
General Principles of Drug Therapy

Topics Outline

ABSORPTION METABOLISM
Ionization Rates of Metabolism
Molecular Weight Microsomal P450 Isoenzymes
Dosage Form Enzyme Induction and Inhibition
Routes of Administration ELIMINATION
DISTRIBUTION Pharmacokinetic Changes with Aging
Plasma Protein Binding
Selective Distribution

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General Principles of Drug Therapy

Pharmacokinetics (PK) study of ADME

Absorption drug in
Distribution
Metabolism
Excretion drug out = Elimination
Movement of drug molecules through various
physiologic compartments drug deposition

Processes that determine drug delivery to (in)
and removal from (out) molecular targets
Drug concentration-Time relationship
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General Principles of Drug Therapy

Pharmacokinetics Overview
PK what the body
Understanding PK
does to a drug
parameters, enable
design of optimal drug
regimens, including :
route of
administration
(RoA),
dosage,
dosing interval, and
duration of Tx
Modified from: Lippincott Illustrated
Reviews: Pharmacology. 6e. (2014)
General Principles of Drug Therapy

Pharmacokinetics Overview (2)

Goodman and Gilman's The Pharmacological Basis of Therapeutics 12e, (2011)

Interrelationship of absorption, distribution,
binding, metabolism, and excretion of a drug and
its concentration at its sites of action 5
General Principles of Drug Therapy

Important Properties Affecting
Drug Absorption

Chemical properties Physiologic variables:
acid or base gastric motility
degree of ionization pH at the absorption site
polarity area of absorbing surface
molecular weight blood flow
lipid solubility presystemic elimination
or...partition coefficient ingestion w/wo food

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General Principles of Drug Therapy

Routes of Drug Administration (RofA)
 Absorption is how the patient’s body
takes in (absorbs) the drug in question
RofA:
 Enteral, meaning absorbed
through intestines: oral and rectal

 Parenteral, meaning absorbed
without intestines: intravenous
(IV), intramuscular (IM),
subcutaneous (SQ ), inhaled,
topical, or transdermal

Lippincott Illustrated Reviews,
Pharmacology. 6e. (2015)
General Principles of Drug Therapy

Enteral Routes
of Administration
General Principles of Drug Therapy

Bioavailability (F)
 F is how much of what is ingested makes it into the systemic
circulation

 Drugs administered intravenously bypass absorption, thus
have a bioavailability of 1 (100%)

 Oral drugs have < 100% bioavailability (< 1) because:
1) not everything is absorbed (incomplete
tablet breakdown, barriers to absorption across gut mucosa,
gastric acid or enzymatic destruction)
2) after absorption through intestines into portal vein, drug
first passes through liver, where some of drug is
metabolized before reaching systemic circulation-termed
first pass metabolism
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General Principles of Drug Therapy

First-pass metabolism
Any substance absorbed through
the intestinal mucosa
(except at end of the rectum)
will drain into the portal system
and be processed by the
liver before reaching the
systemic circulation

From Brenner GM, Stevens CW. Pharmacology.
10
3rd ed. Philadelphia: Elsevier; 2009.
General Principles of Drug Therapy

Oral Ingestion
• Governed by:
surface area for absorption, blood flow, physical
state of drug, concentration
occurs via passive process
In theory: weak acids optimally absorbed in
stomach, weak bases in intestine
In reality: overall rate of absorption of drugs is
always greater in intestine (surface area, organ
function)

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General Principles of Drug Therapy

Forms of Oral Drugs

Fastest  liquids: syrups, elixirs

 Suspensions

 Powders

Slowest  pills: capsules, tablets

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General Principles of Drug Therapy

Rate of Appearance in Blood
 Dependent on rate of dissolution
 Rate of absorption from GI tract

For example:
Timed release capsules
dissolve at different rates

Enteric coating pills
dissolve in alkaline fluid

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General Principles of Drug Therapy

Effect of Changing
Rate of Gastric Emptying
Ingestion of a solid dosage form with a glass of cold
water will accelerate gastric emptying
accelerated presentation of drug to upper intestine
significantly increases absorption
Ingestion with a fatty meal, acidic drink, or with
another drug with anticholinergic properties, will
retard gastric emptying
Sympathetic output (as in stress) also slows
emptying
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General Principles of Drug Therapy

Sublingual (SL) Administration
Absorption from oral mucosa has special significance
for certain drugs despite small surface area
Nitroglycerin (SL-NTG) - nonionic, very lipid soluble
Due to venous drainage into superior vena cava, this
route “protects” from first-pass liver metabolism

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General Principles of Drug Therapy

Rectal Administration
Advantages:
Useful when oral administration is precluded by
vomiting or when patient is unconscious
Approx. 50% of drug absorbed from rectum will
bypass liver, thus reducing influence of first-pass
hepatic metabolism

Disadvantages:
Irregular and incomplete absorption
Irritation
Patient aversion
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General Principles of Drug Therapy

Parenteral Routes
of Administration
General Principles of Drug Therapy

Subcutaneous

 Slow and constant absorption

 Slow-release pellet may be implanted

 Drug must not be irritating

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General Principles of Drug Therapy

Intramuscular
 Rapid rate of absorption from aqueous solution,
depending on the muscle
 Perfusion of particular muscle influences rate of
absorption: gluteus vs. deltoid
 Slow & constant absorption of drug when injected in
an oil solution or suspension

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General Principles of Drug Therapy

Intra-arterial administration
 Occasionally a drug is injected directly into an
artery to localize its effect to a particular
organ, e.g., for liver tumors, head/neck
cancers
 Requires great care and should be reserved
for those with experience

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General Principles of Drug Therapy

Intrathecal administration
 Necessary RofA if the blood-brain barrier
and blood-CSF barrier impede entrance into
CNS

 Injection into spinal subarachnoid space:
used for local or rapid effects of drugs on
the meninges or cerebrospinal axis, as in
spinal anesthesia or acute CNS infections

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General Principles of Drug Therapy

Intraperitoneal administration

 Peritoneal cavity offers a large absorbing
surface area from which drug may enter
the circulation rapidly

 Seldom used clinically

 Infection is always a concern

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General Principles of Drug Therapy

Pulmonary Absorption
 Inhaled gaseous and volatile drugs are
absorbed by the pulmonary
epithelium and mucous membranes
of respiratory tract

 almost instantaneous absorption
 avoids first-pass metabolism
 local application

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General Principles of Drug Therapy

Topical Application
 Mucous membranes
 Drugs are applied to mucous membranes of
conjunctiva, nasopharynx, vagina, colon,
urethra, and bladder for local effects

 Systemic absorption may occur (e.g.
antidiuretic hormone via nasal mucosa)

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General Principles of Drug Therapy

Topical Application (2)
 Skin
 Few drugs readily penetrate skin
 Absorption is proportional to surface area
 More rapid through abraded, burned or denuded skin
 Inflammation increases cutaneous blood flow and,
therefore, absorption
 Enhanced by suspension in oily vehicle and rubbing into
skin

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General Principles of Drug Therapy

Topical Application (3)
 Eye
 topically applied ophthalmic drugs are used
mainly for their local effects
 systemic absorption that results from drainage
through nasolacrimal canal is usually undesirable
 not subject to first-pass hepatic metabolism

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General Principles of Drug Therapy

Routes of Administration Summary Table (1)
RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES

Oral • Variable; affected by many • Safest and most common, • Limited absorption of some drugs
factors convenient, and economical RofA • Food may affect absorption
• Patient compliance is necessary
• Drugs may be metabolized before
systemic absorption
Intravenous • Absorption not required • Can have immediate effects • Unsuitable for oily substances
• Ideal if dosed in large volumes • Bolus injection may result in adverse
• Suitable for irritating substances effects
and complex mixtures • Most substances must be slowly
• Valuable in emergency situations injected
• Dosage titration permissible • Strict aseptic techniques needed
• Ideal for high molecular weight
proteins and peptide drugs
Subcutaneous • Depends on drug diluents: • Suitable for slow-release drugs • Pain or necrosis if drug is irritating
Aqueous solution: prompt • Ideal for some poorly soluble • Unsuitable for drugs administered in large
Depot preparations: slow and suspensions volumes
sustained
Intramuscular • Depends on drug diluents: • Suitable if drug volume is moderate • Affects certain lab tests (creatine
Aqueous solution: prompt • Suitable for oily vehicles and certain kinase)
Depot preparations: slow and irritating substances • Can be painful
sustained • Preferable to intravenous if patient • Can cause intramuscular
must self-administer hemorrhage (precluded during
anticoagulation therapy)
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General Principles of Drug Therapy
Routes of Administration Summary Table (2)
RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES

Transdermal • Slow and sustained • Bypasses the first-pass effect • Some patients are allergic to
(patch) • Convenient and painless patches, which can cause irritation
• Ideal for drugs that are lipophilic and • Drug must be highly lipophilic
have poor oral bioavailability • May cause delayed delivery of drug
• Ideal for drugs that are quickly to pharmacological site of action
eliminated from the body • Limited to drugs that can be
taken in small daily doses
Rectal • Erratic and variable • Partially bypasses first-pass effect • Drugs may irritate the rectal
• Bypasses destruction by stomach acid mucosa
• Ideal if drug causes vomiting • Not a well-accepted route
• Ideal in patients who are vomiting, or
comatose
Inhalation • Systemic absorption may • Absorption is rapid; can have • Most addictive route (drug can
occur; this is not always immediate effects, Ideal for gases enter the brain quickly)
desirable • Effective for patients with respiratory • Patient may have difficulty
Problems, Dose can be titrated regulating dose
• Localized effect to target lungs: lower • Some patients may have
doses used compared to that with difficulty using inhalers
oral or parenteral administration
• Fewer systemic side effects
Sublingual • Depends on the drug: Few • Bypasses first-pass effect • Limited to certain types of drugs
drugs (for example, • Bypasses destruction by stomach acid • Limited to drugs that can be
nitroglycerin) have rapid • Drug stability maintained because taken in small doses
direct systemic absorption the pH of saliva relatively neutral • May lose part of the drug dose if
Most drugs erratically or • May cause immediate pharmacological swallowed 28
incompletely absorbed effects
General Principles of Drug Therapy

Physicochemical Factors In Transfer of
Drugs Across Membranes

 Cell Membranes
 Passive Properties
 Carrier-Mediated Transport

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General Principles of Drug Therapy

Facts...
 “ADME of a drug all involve its passage across cell
membranes”

 Drugs generally pass through cells rather than
between them
 Thus, the plasma membrane is the common
barrier
 Passive diffusion depends on movement down a
concentration gradient

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General Principles of Drug Therapy

1. Molecular Size
 In general, smaller molecules diffuse more readily across
membranes than larger ones because the diffusion
coefficient is inversely related to the sq. root of the MW

 This applies to passive diffusion but NOT to specialized
transport mechanisms (active transport, pinocytosis)

 tight junction: MW <200
 diffusion through large fenestrations in capillaries: MW 20K-
30K

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General Principles of Drug Therapy

2. Lipid-Solubility
Oil:Water Partition Coefficient
The greater the partition coefficient, the higher the
lipid-solubility of the drug, and the greater its diffusion
across membranes

A non-ionizable compound (or the non-ionized form of
an acid or a base) will reach an equilibrium across the
membrane that is proportional to its concentration
gradient

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General Principles of Drug Therapy

Absorbed from stomach in 1 hour (% of dose)
50
580

40

52
30

20

10
1
Other things (MW, pKa) being equal,
absorption of these drugs is 0
barbital secobarbital thiopental
proportional to lipid solubility (pKa 7.8) (pKa 7.9) (pKa 7.6)
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General Principles of Drug Therapy

3. Ionization
• Most drugs are small (MW < 1000) weak electrolytes
(acids/bases)
• This influences passive diffusion since cell membranes are
hydrophobic lipid bilayers that are much more permeable to
the non-ionized forms of drugs

The fraction of drug that is non-ionized depends on its
chemical nature, its pKa, and the local biophase pH...

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General Principles of Drug Therapy

Ionization (2)
 You can think of properties this way:
 ionized = polar = water-soluble
 non-ionized = less polar = more lipid-soluble

 Think of an acid as having a carboxyl: COOH / COO_
 Think of a base as having an amino: NH3+ / NH2

*For both acids and bases, pKa = acid dissociation constant, the pH at
which 50% of the molecules are ionized.
 Example:
weak acid = aspirin (pKa 3.5)
weak base = morphine (pKa 8.0)
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General Principles of Drug Therapy

Weak acid Weak base
H+ extracellular H+
pH BH+
A- B
HA

HA A- B BH+
intracellular
H+ pH H+

* The pH on each side of the membrane determines the equilibrium on each side
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General Principles of Drug Therapy

A Useful Concept...
Drugs tend to exist in the ionized form
when exposed to their “pH-opposite”
chemical environment.
 Acids are increasingly ionized with
increasing pH (basic environment),
whereas…
 Bases are increasingly ionized with
decreasing pH (acidic environment).

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General Principles of Drug Therapy

+
HA acid pH base HB

cromolyn sodium (2.0) diazepam (3.3)
2

furosemide (3.9) 4 chlordiazepaxide (4.8)

sulfamethoxazole (6.0) 6 triamterene (6.1)
phenobarbital (7.4) cimetidine (6.8)
7.4

phenytoin (8.3) 8 morphine (8.0)

- chlorthalidone (9.4) 10 amantadine (10.1) B
A

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General Principles of Drug Therapy

Henderson-Hasselbalch Eqn.
[protonated]
log = pKa - pH
[unprotonated]

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General Principles of Drug Therapy

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General Principles of Drug Therapy

Problem: What percentage of phenobarbital (weak acid, pKa = 7.4)
exists in the ionized form in urine at pH 6.4?

pKa - pH = 7.4 - 6.4 = 1 take antilog of 1 to get the ratio
between non-ionized (HA) and
antilog of 1 = 10 ionized (A-) forms of the drug:

if pH = pKa then HA = A-
if pH < pKa, acid form (HA) will always predominate
if pH > pKa, the basic form (A-) will always predominate

Ratio of HA/A- = 10/1

% ionized = A- / A- + HA X 100 = 1 / (1 + 10) X 100 = 9% ionized
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General Principles of Drug Therapy

Problem: What percentage of cocaine (weak base, pKa =8 .5)
exists in the non-ionized form in the stomach at pH 2.5?
take antilog of 6 to get the ratio
pKa - pH = 8.5 - 2.5 = 6
between ionized (BH+) and non-ionized
antilog of 6 = 1,000,000 (B) Forms of the drug:

if pH = pKa then BH+ = B
if pH < pKa, acid form (BH+) will always predominate
if pH > pKa, the basic form (B) will always predominate
Ratio of BH+/B = 1,000,000/1

% non-ionized = B / (B + BH+) X 100 = 1 X 10-4 % non-ionized or 0.0001%

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General Principles of Drug Therapy

In a Suspected Overdose...
 The most appropriate site for sampling to identify the
drug depends on the drug’s chemical nature

 Acidic drugs concentrate in plasma, whereas the
stomach is a reasonable site for sampling basic drugs

 Diffusion of basic drugs into the stomach results in
almost complete ionization in that low-pH environment

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General Principles of Drug Therapy

naproxen (weak acid, pKa 5.0)
gastric juice plasma
pH 2.0 pH 7.4
HA = 1.0 HA = 1.0
+ +
A- = 0.001 A- = 251

total total
HA + A- = 1.001 HA + A- = 252

morphine (weak base, pKa 8.0)
small intestine plasma
pH 5.3 pH 7.4
HB+ = 501 HB+ = 4
+ +
B = 1.0 B = 1.0

total total
+ +
HB + B = 502 HB + B = 5
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General Principles of Drug Therapy

Other aspects….

 amphetamine (weak base, pKa 10)
 its actions can be prolonged by ingesting bicarbonate to
alkalinize the urine...
 this will increase the fraction of amphetamine in non-ionized
form, which is readily reabsorbed across the luminal surface of
the kidney nephron...
 in overdose, you may acidify the urine to increase kidney
clearance of amphetamine

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General Principles of Drug Therapy

Other aspects….
 Certain compounds may exist as strong electrolytes
 This means they are ionized at all body pH values
 They are poorly lipid soluble
Examples:
strong acid = glucuronic acid derivatives of drugs.
strong base = quaternary ammonium compounds such as
acetylcholine

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General Principles of Drug Therapy

Membrane Transfer

passive carrier-mediated endocytosis
diffusion active passive

ATP

ADP-Pi

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General Principles of Drug Therapy

Facilitated Diffusion
 This is a carrier-mediated process that does NOT
require energy
 Movement of substance can NOT be against its
concentration gradient
 Necessary for transport of endogenous
compounds whose rate of movement across
membranes by simple diffusion would be too slow
Example: Insulin
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General Principles of Drug Therapy

Special carriers
 Substances that are important for cell function
and too large or too insoluble in lipid to diffuse
passively through membranes
 eg, peptides, amino acids, glucose.

 These kind of transport, unlike passive diffusion,
is saturable and inhabitable

Active transport - requirement of energy
Facilitated diffusion - needs no energy
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General Principles of Drug Therapy

Special carriers (2)
Carrier-mediated transport is important
for some drugs that are chemically related
to endogenous substances
The transporter proteins also mediate
drug efflux
 P-glycoprotein /MDR1
 MRP transporters
Function as a barrier system to protect
cells

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General Principles of Drug Therapy

MDR1/P-glycoprotein

P-glycoprotein: P-glycoprotein 1
(permeability glycoprotein, abbreviated
as P-gp or Pgp) also known as
multidrug resistance protein 1 (MDR1)
or ATP-binding cassette subfamily B
member 1 (ABCB1) is an important
protein of the cell membrane that
pumps many foreign substances out of
cells.

Produced by the mdr-1 gene
(Characterization of the human MDR1 gene. 2005).
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General Principles of Drug Therapy

Active Transport
 Occurrence:
 neuronal membranes, choroid plexus, renal tubule cells,
hepatocytes
 Characteristics:
 carrier-mediated
 Selectivity
 competitive inhibition by congeners
 energy requirement *
 Saturable
 movement against concentration gradient *

*differences from facilitated diffusion
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General Principles of Drug Therapy

Endocytosis, Exocytosis, Internalization
Endocytosis (or pinocytosis): a portion of the plasma
membrane invaginates and then pinches off from the
surface to form an intracellular vesicle

Example:
This is the mechanism by which thyroid follicular cells, in
response to TSH, take up thyroglobulin (MW > 500,000).

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General Principles of Drug Therapy

Drug Absorption and Bioavailability (F)
 Absorption describes the rate and extent at which a drug
leaves its site of administration

 Bioavailability (F) is the extent to which a drug reaches its
site of action, or to a biological fluid (such as plasma) from
which the drug has access to its site of action

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General Principles of Drug Therapy

Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free

Systemic
circulation

Absorption Free drug Excretion

Bound drug Metabolites

Biotransformation
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General Principles of Drug Therapy

AUC = area under the curve
AUC oral

plasma concentration of drug
Bioavailability = AUC injected i.v. X 100

AUC
injected i.v.

AUC
oral

time
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General Principles of Drug Therapy

Factors Modifying Absorption
 drug solubility (aqueous vs. lipid)
 local conditions (pH)
 local circulation (perfusion)
 surface area

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General Principles of Drug Therapy

Bioequivalence
 Drugs are pharmaceutical equivalents if they contain the same
active ingredients and are identical in dose (quantity of drug),
dosage form (e.g., pill formulation), and route of
administration
 Bioequivalence exists between two such products when the
rates and extent of bioavailability of their active ingredient are
not significantly different

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General Principles of Drug Therapy

Distribution
 Once a drug is absorbed into the bloodstream, it may be
distributed into interstitial and cellular fluids

 The actual pattern of drug distribution reflects various
physiological factors and physicochemical properties of the
drug

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General Principles of Drug Therapy

Phases of Distribution
 first phase
 reflects cardiac output and regional blood flow
 Thus, heart, liver, kidney & brain receive most of the drug during
the first few minutes after absorption
 next phase
 delivery to muscle, most viscera, skin and adipose is slower,
and involves a far larger fraction of the body mass

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General Principles of Drug Therapy

Drug Reservoirs
 Body compartments where a drug can accumulate are reservoirs
 Have dynamic effects on drug availability.

 plasma proteins as reservoirs (bind drug)
 cellular reservoirs
 Adipose (lipophilic drugs)
 Bone (crystal lattice)
 Transcellular (ion trapping)

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General Principles of Drug Therapy

Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free

Systemic
circulation

Absorption Free drug Excretion

Bound drug Metabolites

Biotransformation
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General Principles of Drug Therapy

Protein Binding
 Passive movement of drugs across biological membranes
is influenced by protein binding
 Binding may occur with plasma proteins or with non-
specific tissue proteins in addition to the drug’s receptors

***Only drug that is not bound to proteins (i.e., free or
unbound drug) can diffuse across membranes

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General Principles of Drug Therapy

Plasma Proteins
 albumin
- binds many acidic drugs
 α1-acid glycoprotein
- binds basic drugs
 The fraction of total drug in plasma that is bound is
determined by
1. its concentration
2. its binding affinity
3. the number of binding sites
 At low concentration, binding is a function of Kd (dissociation
constant); at high concentration it’s the # of binding sites
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General Principles of Drug Therapy

Plasma Proteins (2) Example
Thyroxine (thyroid hormone T4)
 > 99% bound to plasma proteins (PPB)
 The main carrier is the acidic glycoprotein thyroxine-binding
globulin [Thyroxine Binding Globulin (TBG)]
 very slowly eliminated from the body, and has a very long half-
life

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General Principles of Drug Therapy

Drugs Binding Primarily to Albumin
barbiturate probenecid
benzodiazepines streptomycin
bilirubin sulfonamides
digotoxin tetracycline
fatty acids tolbutamide
penicillins valproic acid
phenytoin warfarin
phenylbutazone

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General Principles of Drug Therapy

Drugs Binding Primarily to
α1-Acid Glycoprotein
alprenolol lidocaine
bupivicaine methadone
desmethylperazine prazosin
dipyridamole propranolol
disopyramide quinidine
etidocaine verapamil
imipramine

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General Principles of Drug Therapy

Drugs Binding Primarily to
Lipoproteins
amitriptyline
nortriptyline

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General Principles of Drug Therapy

Bone Reservoir
 Tetracycline antibiotics (and other divalent metal ion-chelating
agents) and heavy metals may accumulate in bone
 They are adsorbed onto the bone-crystal surface and eventually
become incorporated into the crystal lattice

 Bone then can become a reservoir for slow release of toxic
agents (e.g., lead, radium) into the blood

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General Principles of Drug Therapy

Adipose Reservoir
• Many lipid-soluble drugs are stored in fat

• In obesity, fat content may be as high as 50%, and in
starvation it may still be only as low as 10% of body weight

• 70% of a thiopental dose may be found in fat 3 hr. after
administration (see next slide)

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General Principles of Drug Therapy

Thiopental
A highly lipid-soluble i.v. anesthetic
 Blood flow to brain is high, so maximal brain concentrations
brain are achieved in minutes and quickly decline
 Plasma levels drop as diffusion into other tissues (muscle)
occurs
 Onset and termination of anesthesia is rapid
 The third phase represents accumulation in fat (70% after 3 h)
 Can store large amounts and maintain anesthesia

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General Principles of Drug Therapy

Thiopental (2) Graphic Illustration
100
blood
(as percent of initial dose)
Thiopental concentration

brain
muscle adipose
50

0
1 10 100 1000
minutes
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General Principles of Drug Therapy

GI Tract as Reservoir
 Weak bases are passively concentrated in stomach from blood
because of large pH differential

 Some drugs are excreted in bile in active form or as a conjugate
that can be hydrolyzed in intestine and reabsorbed

In the above two cases, and when orally administered drugs
are slowly absorbed, GI tract serves as a reservoir

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General Principles of Drug Therapy

Redistribution
 Termination of drug action is normally by biotransformation /
excretion, but may also occur as a result of redistribution
between various compartments
 Particularly true for lipid-soluble drugs that affect brain and heart

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General Principles of Drug Therapy

Placental Transfer
 Drugs cross the placental barrier primarily by simple passive
diffusion
 Lipid-soluble, nonionized drugs readily enter fetal bloodstream
from maternal circulation
 Rates of drug movement across placenta tend to increase
towards term as tissue layers between maternal blood and
fetal capillaries thin

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General Principles of Drug Therapy

Clinical Pharmacokinetics
Fundamental hypothesis:
 A relationship exists between the pharmacological or toxic
response to a drug and the accessible concentration of the
drug (e.g., in blood)

Important parameters:
 volume of distribution (Vd)
 clearance (CL)
 bioavailability (F)
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General Principles of Drug Therapy

Volume of Distribution
 Volume of distribution (Vd) relates the amount of drug in
the body to the plasma concentration of drug (Cp)

**The apparent volume of distribution is a calculated space
and does not always conform to any actual anatomic
space**

Note: Vd is the fluid volume the drug would have to be
distributed in if Cp were representative of the drug
concentration throughout the body
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General Principles of Drug Therapy

Total body water
plasma volume
extracellular
plasma
3 liters
interstitial
volume interstitial volume
15 liters
intracellular
volume
intracellular 12 liters
42 liters

27 liters
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General Principles of Drug Therapy

At steady-state plasma concentration (Css):

total drug in body (mg)
Vd = ------------------------------
plasma conc. (mg/ml)

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General Principles of Drug Therapy

Example of Vd
• The plasma volume of a 70-kg man ~ 3L, blood volume ~
5.5L, extracellular fluid volume ~ 12L, and total body
water ~ 42L.
• Givens: If 500 mg of digoxin were in his body, Cp would be
~ 0.7 ng/ml
• Dividing 500 mg by 0.7 ng/ml yields a Vd of 700L, a value
10 times total body volume! Huh?

• Digoxin is hydrophobic and distributes preferentially to
muscle and fat, leaving very little drug in plasma
• The digoxin dose required therapeutically depends on
body composition
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General Principles of Drug Therapy

Clearance (CL)
• Clearance is the most important property to consider when a
rational regimen for long-term drug administration is designed
– The clinician usually wants to maintain steady-state drug
concentrations known to be within the therapeutic range
– CL = dosing rate / Css
– CL = rate of elimination / Css
– (volume/time) = (mass of drug/time) / (mass of drug/volume)

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General Principles of Drug Therapy

Clearance (2)
• Clearance does not indicate how much drug is removed but,
rather, the volume of blood (or plasma) that would have to be
completely freed of drug to account for the elimination rate.
– CL is expressed as volume per unit time

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General Principles of Drug Therapy
Clearance (3)
Sum of all process
contributing to
disappearance of drug
from plasma
Drug in plasma at Drug concentration in plasma is less
concentration of 2 mg/ml after each pass through elimination /
metabolism process

Remember:
CL = dosing rate / Css
CL = rate of elimination / Css
Drug molecules disappearing from
plasma at rate of 400 mg/min

CL = 400 mg/min
= 200 ml/min
2 mg/ml

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General Principles of Drug Therapy

Clearance (4)
Example: cephalexin, CLp = 4.3 ml/min/kg

• For a 70-kg man, CLp = 300 ml/min, with renal clearance
accounting for 91% of this elimination

• So, the kidney is able to excrete cephalexin at a rate such that
~ 273 ml of plasma is cleared of drug per minute
• Since clearance is usually assumed to remain constant in a
stable patient, the total rate of elimination of cephalexin
depends on the concentration of drug in plasma

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General Principles of Drug Therapy

Clearance (5)
Example: propranolol, CLp = 12 ml/min/kg or 840
ml/min in a 70-kg man
The drug is cleared almost exclusively by the liver
Every minute, the liver is able to remove the amount of drug
contained in 840 ml of plasma
NB:
Clearance of most drugs is constant over a range of
concentrations
This means that elimination is not saturated and its rate is
directly proportional to the drug concentration:
this is a description of 1st-order elimination
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General Principles of Drug Therapy

CL in a given organ
CL in a given organ may be defined in terms of blood flow and
[drug]
Q = blood flow to organ (volume/min)
CA = arterial drug conc. (mass/volume)
CV = venous drug conc.
rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)

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General Principles of Drug Therapy

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General Principles of Drug Therapy

Further study:
 eNotes: GP- General Principles of Drug Action

 Drug-Receptor Interactions, Morris ZS, Golan DE and (or)

 Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors and
Concentration-Response Relationships
 Enzyme kinetics Notes

 MedPharm Wiki| PK and PD, Pgs. 73-88

 Pharmacology Course Website

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