Pharmacokinetics Processes, Absorption, Distribution,

Metabolism, Excretion, and Individualized Therapy

Dr. O.S. Michael

Consultant clinical pharmacologist
Department of Pharmacology and Therapeutics
UI / UCH, Ibadan
06Mar 2019
 Objectives
• Understand the basic principles of Pharmacokinetics
• ADME: Absorption, Distribution, Metabolism, and Elimination
• Define Vd, T1/2, Clearance, Tmax,
• Understand the concept of steady state
• Loading dose
• Bioavailability
• First Pass effect
• First and Zero order kinetics
• Factors affecting pharmacokinetics
Why Study Pharmacokinetics (PK)
• Individualize patient drug therapy
• Monitor medications with a narrow therapeutic index
• Decrease the risk of adverse effects while maximizing
pharmacologic response of medications
• Evaluate PK/PD as a diagnostic tool for underlying disease
states
 Pharmacokinetics (PK) & pharmacodynamics (PD)

• PK - What the body does to the drug? (ADME)

– Absorption
– Distribution
– Metabolism
– Excretion

• PD - What the drug does to the body?

– Drug concentration at the site of action or in the plasma is related to a
magnitude of effect

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 Pharmacokinetics (PK) and
pharmacodynamics (PD)

Plasma Site
Concen- of
Dose Effects
tration Action

PK PD

6
Time to Peak Concentration
100
co n cen tra tio n

90
80
70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 5 10 20 30 60 120 180
minutes
 Drug Absorption

• In order to reach their site of action, drugs have to pass through several
membranes
• The specific membranes depend on the site of action and the route of
administration
– Many different routes of administration
• Oral
• Injection (or parenterally)
• Inhalation
• Absorption through the skin or membranes

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 Types of Absorption across
Membranes
 If the drug ion is small, it can cross the membrane via aqueous channels
(not most drugs)
 Occurs by dissolving in fat (lipid solubility)
 Occurs by active transport proteins with charged surfaces (positive or
negative charge)
 If the drug ion is small, it can cross the membrane via aqueous channels
(not most drugs)
 Occurs by dissolving in fat (lipid solubility)
 Occurs by active transport proteins with charged surfaces (positive or
negative charge)

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 Factors that affect absorption
 The particle size of the dosage form
 Smaller is better if lipid-solubility is low
 The relative concentration of the molecule on the two sides of the membrane
 More concentrated drugs will be absorbed better
 The pH levels
 The drug’s lipid-solubility (also known as the lipophilicity)
– Lipophilic molecules are more soluble in fats and oils.
 The drug’s water-solubility (also known as hydrophilicity
 Hydrophilic molecules are more soluble in aqueous solutions.
 Once in solution, drugs exist as a mixture of two interchangeable forms
 Water-soluble (the ionized or electrically charged form)
 Lipid-soluble (the non-ionized, or uncharged form)

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 Factors that affect absorption 2
• Drug molecules that have an electrical charge (ionized) are not lipid soluble
• When dissolved in liquid, some or all of a drug’s molecules become ionized; what
percentage is determined by:
– Whether the drug itself is an acid or a base
– Whether it is dissolved in an acid or base
– Its pKa
• The pKa of a drug is the pH at which 50% of its molecules are ionized
• pH < 7 is acidic
• pH > 7 is basic or more alkaline
• pH = 7 is neutral

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 Routes of Administration

 Oral  Transdermal (patch)

 Injection  Mucous membranes of
 Intravenous  mouth or
 Subcutaneous  nose (includes nasal sprays)
 Intramuscular
 Inhalation
 Intra-peritoneal
 Intra-arterial etc.  Rectal or vaginal

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 Oral Route
Advantages Disadvantages
 Relatively Fast • Onset of action not very fast
 Painless (usually) • Some drugs don’t withstand stomach/GI
 conditions (insulin, cocaine)
Easy to administer
• Drug absorption more variable
 Safe
• May cause GI distress
 No need for equipment, help or special • Not suitable for uncooperative, vomiting,
training unconscious patients
 Most drugs can be given orally • FIRST PASS through liver

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 Factors influencing absorption
through the GI tract
 Ionization (a state in which an atom or molecule has a net electrical charge)
reduces an ion’s solubility in cellular membranes because the proteins in the
membrane have a mix of positive and negative charges that tend to repel
charged particles.
 Ionized = water soluble; unionized = lipid soluble

 Local pH or alkalinity and acidity is what controls the ratio of ionized to

unionized drug
 Higher concentrations of drug and slow movement through the GI tract
favors absorption
 Food can bind to the drug or dilute it to slow it down

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 Parenteral Route: Intravenous/Intramuscular
Disadvantages Advantages

• Fast • Painful

• Bypasses first pass • Too fast to respond if bad reaction or

overdose
• Bypasses digestion
• Potential for infection
• More accurate dose
• Unless IV intended, must be careful to
• Can be done by person with training avoid veins
• No chance for recall of drug

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 Intravenous route
Advantages Disadvantages
• Very rapid method (15 sec to brain) • Much care needed if reaction or
• Dose can be precise allergy possible
• Can start and stop injection, or do it • Overdose can’t be corrected unless
slow there is an antidote on hand
• Can give large volume with small • Infection can be devastating
concentrations of drug (avoid • Repeated injection can damage veins
irritation) • Drug must be completely water
• Smaller doses needed E.g., PCP, soluble
heroin, morphine

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 Subcutaneous: just beneath skin, into body
fat
Advantages
 Slowest of injection routes, but is still
rapid
 Easy
 Can most reasonably be done by the
individual e.g. insulin
 Suspension or pellets possible
(repository preparation s)
Disadvantages
• Can be irritating to local tissue
• Large volumes may n ot be
appropriate
• Distribution not always controlled
• Infection possible
• Need for trained personnel
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 Basic Parameters

In pharmacokinetics the body is represented as a single or multiple

compartments into which the drug is distributed.

Some of the parameters are a little abstract as the body is more

complicated

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 Important Concepts
• Vd is a theoretical Volume and determines the loading dose
• Clearance is a constant and determines the maintenance dose
• CL = kVd
• CL and Vd are independent variables
• k is a dependent variable

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 Volume of Distribution (Vd)

 Apparent volume of distribution is the theoretical

volume that would have to be available for a drug
to disperse in if the concentration everywhere in the
body were the same as that in the plasma or
serum, the place where drug concentration
sampling generally occurs.

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 Volume of Distribution
• An abstract concept

• Gives information on HOW the drug is distributed in the body

• Used to calculate a loading dose

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 Clearance
 Ability of organs of elimination (e.g. kidney, liver to “clear” drug
from the bloodstream

 Volume of fluid which is completely cleared of drug per unit time

 Units are in L/hr or L/hr/kg

 Pharmacokinetic term used in determination of maintenance

doses

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 Vd and Clearance
• Volume of Distribution =

• Dose_______
• Plasma Concentration

Clearance =
Volume of blood cleared of drug per unit time
 Half-Life and k
• Half-life is the time taken for the drug concentration
to fall to half its original value

• The elimination rate constant (k) is the fraction of

drug in the body which is removed per unit time.

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 Log Concn.
C0

C0/2
t1/2

t1/2

t1/2

Time
Time to eliminate ~ 4 t1/2
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 Plasma half-life

• • A drug’s half-life (measured in time) determines how often it must be taken and how long it takes
for the drug to wear off and to leave one’s system.
# of Half-lives Percent eliminated
0 0
1 50
2 75
3 87.5
4 93.8
5 96.9
6 98.4
• This assumes normal liver and kidney function. Older, younger, or sick people may clear drugs more
slowly

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 Steady-State
 Steady-state occurs after a drug has been given for approximately
five elimination half-lives.

 At steady-state the rate of drug administration equals the rate of

elimination and plasma concentration - time curves found after
each dose should be approximately superimposable.

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 What is Steady State (SS) ?
Why is it important ?

• Rate in = Rate Out

• Reached in 4 – 5 half-lives (linear kinetics)

• Important when interpreting drug concentrations in TDM or

assessing clinical response

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 Loading dose

• Loading dose allows rapid achievement of therapeutic blood level

• Same loading dose used regardless of metabolism/elimination

dysfunction

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 pKa
• pKa value is a constant for each type of molecule.
• It is unaffected by concentration.
• pH = pKa + log ([conjugate base]/[weak acid])
• pH = pka+log ([A-]/[HA])
 pKa
• A large number of drugs are weak bases.
• Weak bases are ionized and therefore more polar and more water
soluble when they are protonated.
• Weak acids are less ionized and thus less water soluble when they
are protonated.
• Protonated means associated with a proton (a hydrogen ion).
• pH of a medium determines the fraction of molecules charged
(ionized) if the molecule is a weak acid or a weak base. If the pKa of
the drug and the pH of the medium are known, the fraction ionized
can be predicted.
 pKa
• Log (protonated form/unprotonated form) = pKa – pH
• (Henderson-hasselbalch equation)
• Example
• Aspirin is a weak organic acid with a pKa of 3.5. What percentage of a given dose
will be in the lipid-soluble form at a stomach pH of 2.5?
• The drug is an acid. Protonated form is more non-ionized, more lipid soluble.
• When pKa = pH, there in 50/50 protonated/unprotonated. At 1 pH unit more acid
than pKa, the protonated/unprotonated form is 10/1 (log 10 = 1), if for ten
molecules of aspirin, 9 will be protonated (non-ionized), while 1 will ne
unprotonated (ionized)
• The solution is 90%
• At a more basic pH than pKa, aspirin will be unprotonated (ionized) and thus less
lipid soluble.
 Linear and non-linear PK
Linear PK (First order kinetics)
Rate of elimination is proportional to amount of drug present (concentration
of drug in plasma)
Dosage increases results in proportional increase in plasma drug level
The T/2 of the drug is constant regardless of the amount in the body
Concentration will decrease by 50% with every T1/2
Most drugs are in this category

Non-linear PK (zero order kinetics)

Rate of elimination is constant irrespective of amount of drug present
Dosage increases saturate binding sites and results in non-proportional
increases and decreases in drug level
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Elimination kinetics First order Zero order

Curve in the plasma

concentration vs. time plot exponential decay Linear
after i.v. bolus

Curve in the log plasma

concentration vs. time plot Linear non-linear
after i.v. bolus

Relation between elimination rate is elimination rate saturates

elimination rate and drug proportional to drug with higher drug
concentration concentration concentration
Term in clinical
linear kinetics non linear kinetics
pharmacology
95 % of drugs, at therapeutic the remaining 5 %, and
Concerns
concentrations ethanol
 Some more terminologies
 Bioavailability (F)
 measure of the amount of drug absorbed into the general
circulation
 Area under the curve (AUC)
 obtained from the plasma concentration versus time plot
 gives a measure of the amount of drug absorbed
 Foral = AUCoral /AUCiv
 Clearance = F. dose/AUC
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 Special patient groups
• Renal disease
– Same hepatic metabolism, same or increased volume of
distribution and prolonged elimination
– ---INCREASE DOSING INTERVAL
• Hepatic disease
– Same renal elimination, same volume of distribution, slower rate of
enzymatic metabolism
– ----REDUCE DOSAGE AND INCREASE DOSING INTERVAL

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Metabolism: Phase I reactions
• Cytochrome P450 system
• Located within the endoplasmic reticulum of hepatocytes
• Through electron transport chain, a drug bound to the
CYP450 system undergoes oxidation or reduction
• Enzyme induction
• Drug interactions
Phase II reactions
• Polar group is conjugated to the drug
• Results in increased polarity of the drug
• Types of reactions
– Glycine conjugation
– Glucuronide conjugation
– Sulfate conjugation
Phase I reactions types
• Hydrolysis
• Oxidation
• Reduction
• Demethylation
• Methylation
• Alcohol dehydrogenase metabolism
 Metabolism
• Cleavage = splitting of the molecule into 2 or more simpler molecules
• Oxidation = combining the molecule with oxygen, or increasing the
electropositive charge by the loss of hydrogen or of one or more
electrons
• Conjugation = the combining of the molecule with glucuronic or sulfuric
acid
• Reduction = the molecule gains 1 or more electrons and becomes more
negatively charged

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 First Pass Effect
• Metabolism begins in the G.I. tract for orally administered drugs
• Drugs that pass through the stomach/small intestine end up in the
hepatic portal vein and visit the liver first – referred to as first-pass
metabolism
• For most drugs first-pass metabolism is primarily hepatic (liver),
although metabolism of alcohol occurs predominantly at an upper G.I.
site
• The liver is the organ most responsible for metabolizing drugs
regardless of the rout of administration.

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 The role of the liver in drug metabolism

• Drugs diffuse out of the blood into liver cells (hepatocytes) where they
are acted on by the cytochrome P450 enzymes
• Metabolites and the drug will diffuse back into the blood plasma and/or
be secreted into the bile
• Metabolites that are sufficiently water-soluble will be excreted via urine,
if not water-soluble they will recirculate and may be further metabolized
in the liver
• Metabolites in the bile that are water-soluble will be excreted via feces, if
not water-soluble they will be reabsorbed, and undergo further
metabolism
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 Factors affecting drug metabolism

 Drug Dose
 The higher the plasma concentration of a drug the higher the rate of metabolism (first-order kinetics) for
most drugs (but not alcohol)
 A drug that is easily metabolized by the liver must be given in higher doses
 If a person’s liver is altered or damaged, the effectiveness of a drug given orally may be greatly
changed
 Enzyme changes
 Many drugs cause induction of liver enzymes (increases due to continued use); this reduces the
effectiveness of those drugs and other drugs that are metabolized by those enzymes (one aspect of
tolerance)
 Some drugs inhibit the activity of enzymes, which will increase the effect of all drugs metabolized by that
enzyme
 Some drugs have direct effects on rate of metabolism of other drugs
 E.g., they may compete for the same enzyme
 Individual differences
 Sex, Age, Species, Past experience with drugs

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 Other forms of drug excretion

• Many drugs and their metabolites may be found in other

secretions, but their concentrations are generally low
– Excretion of drugs via sweat, tears, or salivation is minuscule
– Small amounts are excreted in breast milk, but small amounts may be
too much for babies
– Excretion occurs from the lungs with some drugs Lungs can excrete
volatile substances (which may not be water-soluble) e.g. General
anaesthesia, Paraldehyde
– Bile (faeces)

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 Factors affecting Clinical Pharmacokinetics
• Age: extremes of age associated
with decreased metabolism and
excretion
• Gender: Total body water in
females less than that in males
• Obesity: volume of distribution
for lipid soluble drugs greater in
obese subjects
• Food-drug interaction
• Disease: Liver and kidney disease
may reduce drug metabolism and
excretion significantly
• Dialysis : drug excretion may be
more
• Smoking: may induce liver
enzymes and result in faster drug
metabolism
• Drug-drug interactions
• Age
• Race/ethnicity
• Weight
• Gender PERSONALIZED
• Concomitant Diseases MEDICINE
• Concomitant Drugs
• Social factors
• GENETICS
 The SQ4R Method of Reading
• SURVEY: Take a look at the
material: skim the chapter
headings and the boldface words
• QUESTIONS: Make up questions
about the things you found in the
preview and from the learning
objectives
• READ: As you read, try to answer
the questions you developed.
Make notes as you read.
• RECITE: Say the material over to
yourself; put it into your own
words
• wRITE (or RECALL): Write down
summaries in your own words
• REVIEW: Try to recall the
material and test yourself. You
should review several times
during your studying so you know
what to concentrate on.
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