PHARMACOKINETICS

‘The quantitative study of drug movement in,

through and out of the body’

BY: A D E O LU WA
O. A .
D E P A R T M E N T O F P H A R M A C O L O G Y,
C O L L E G E O F M E D I C I N E A N D H E A LT H
SCIENCES, AFE BABALOLA UNIVERSITY
Pharmacokinetics (PK)

 The study of the disposition of a drug

 The disposition of a drug includes the
processes of ADME
 Absorption

 Distribution
 Metabolism/Biotransformation
Elimination
 Excretion
INTRODUCTION
 Unless a drug acts topically (i.e., at its site of
application), it first must enter the bloodstream and
then be distributed to its site of action.

 The mere presence of a drug in the blood, however,

does not lead to a pharmacological response. To be
effective, the drug must leave the vascular space and
enter the intercellular or intracellular spaces or both.

 All pharmacokinetic processes involve transport of

the drug across biological membranes.
Factors that affect drug concentration at its site of action.
Once a drug has been absorbed into the blood, it may be
subjected to varying degrees of metabolism, storage in non-
target tissues, and excretion. The quantitative importance of
each of these processes for a given drug determines the
ultimate drug concentration achieved at the site of action .
THE CELL MEMBRANE
 Cholesterol (e.g., sphingolipids),
a
Extracellular fluid endows the membrane with
fluidity, flexibility, organization,
Glycoprotein Integral proteins and electrical resistance. The lipid
Glycolipid components confer high
permeability to lipids and low
permeability to water-soluble
substances.
 Individual lipid molecules in the
bilayer vary according to the
particular membrane and can
Phospholipid
move laterally and organize
Cholesterol
Peripheral proteins
themselves.
Channel
 A smaller component consists of
Cytoplasm
glycoproteins or lipoproteins that
are embedded in the lipid matrix
The plasma membrane consists of and have ionic and polar groups
protruding from one or both sides
a bilayer of phospholipids and
of the membrane.
cholesterol molecules with their
hydrocarbon chains oriented inward  Membrane proteins embedded in
to the center of the bilayer to form the bilayer serve as receptors, ion
a continuous hydrophobic phase channels, and transporters to
and their hydrophilic heads oriented transduce electrical or chemical
MECHANISMS OF DRUG TRANSPORT
ACROSS MEMBRANES
Drugs are transported across the membrane by:
1. Passive diffusion
2. Filtration
3. Specialized transport
4. Others mechanisms (e.g bulk transport, exocytosis).

1. Passive (simple) diffusion:

 In passive transport, the drug molecule diffuses along a
concentration gradient across the membrane by virtue of its
solubility in the lipid bilayer, the membrane playing no active role
in the process.
 Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of
the membrane, the rate of transport being proportional to lipid :
water partition coefficient of the drug.
 A more lipid soluble drug attains higher concentration in the
membrane and diffuses quickly
 Diffusion is directly proportional to the magnitude of the
concentration gradient across the membrane.

PHYSICOCHEMICAL PROPERTIES OF DRUGS AND THE
INFLUENCE OF PH
 The ability of a drug to diffuse across membranes is frequently
expressed in terms of its lipid–water partition coefficient rather
than its lipid solubility per se.

 The partition coefficient is a measure of the relative affinity of a

drug for the lipid and aqueous phases.

 Increasing the polarity of a drug (i.e. making the drug more water
soluble) decreases the lipid–water partition coefficient.
Alternatively, reducing drug polarity results in an increase in the
lipid–water partition coefficient.

 Hence, the higher the partition coefficient of a drug, the easier

the ability to diffuse across the membrane.

 Drugs are not completely ionized in aqueous solution. The smaller

the fraction of total drug molecules ionized, the weaker the
electrolyte.
 The transmembrane distribution of a weak electrolyte
is determined by its pKa (pH at which 50% is ionized)
and the pH gradient across the membrane.

 The ratio of non-ionized to ionized drug at each pH is readily

calculated from the
Henderson–Hasselbalch equation:

 At steady state, an acidic drug will accumulate on the more basic

side of the membrane and a basic drug on the more acidic side—
IMPLICATIONS OF THE pKa VALUE
 The use of only pKa values to describe the relative strengths of either
weak bases or weak acids makes comparisons between drugs simpler.
 The lower the pKa value (pKa 6) of an acidic drug, the stronger the
acid (i.e., the larger the proportion of ionized molecules).
 The higher the pKa value (pKa 8) of a basic drug, the stronger the
base.
 Thus, knowing the pH of the aqueous medium in which the drug is
dissolved and the pKa of the drug, one can, using the Henderson-
Hasselbach equation, calculate the relative proportions of ionized and
un-ionized drug present in solution.
 For example, when the pKa of the drug (e.g., 7) is the same as the pH
(e.g., 7) of the surrounding medium, there will be equal proportions of
ionized [R] and un-ionized [RH] molecules; that is, 50% of the drug is
ionized.

Example : Acetaminophen, a weak acid has pKa value of 9.5.

i. Calculate the ratio of ionized to unionized drug in (a) the stomach, pH
1.4, (b) the plasma pH 7.4, (c) the intestinal lumen pH 5.
ii. From the answer above, discuss the major site of absorption of
acetaminophen.
MECHANISMS OF DRUG TRANSPORT
ACROSS MEMBRANES (CONT’D)
2. Filtration:
 Filtration is passage of drugs through aqueous pores
in the membrane localized in paracellular spaces.

 The moving force is hydrostatic or osmotic pressure.

 Lipid insoluble drugs cross the biomembrane by

filtration only if their molecular size is smaller than
the diameter of the enlarged aqueous pores.

 Thus, the rate of filtration depends both on the

existence of a pressure gradient as a driving force and
on the size of the compound relative to the size of the
pore through which it is to be filtered.
3. Specialized transport
Specialized transport can be carrier-mediated or by endocytosis

A.Carrier mediated transport

 Drugs combine with a carrier molecule present in the membrane and the
complex then translocate from one face of the membrane to another.

 The carrier molecule acts as a ferry –boat across the lipid region of the
membrane.

 This mechanism is important for compounds that lack sufficient lipid solubility
to move rapidly across the membrane by simple diffusion.

 Carrier transport is specific, saturable, and competitively inhibited by

analogues which utilizes the same carrier.

 There are two types :

i. Active transport
ii. Facilitated diffusion

 Carrier-mediated drug transport can occur in only a few sites in the body, and
the main sites are: Blood brain barrier (BBB), neuronal membranes, choroid
i. Active transport:
 It is the energy-dependent movement of compounds across membranes,
most often against their concentration gradient. Active transport of a
particular substance occurs in one direction only.

 It is often coupled to energy-producing enzymes (e.g., ATPase) or to the

transport of other molecules (e.g., Na+, Cl−, H+) that generate energy as
they cross the membranes.

 Since active transport often requires energy in the form of adenosine

triphosphate (ATP), compounds or conditions that inhibit energy
production (e.g., iodoacetate, fluoride, cyanide, anaerobiosis) will impair
active transport.

 In general, drugs will not be actively transported unless they sufficiently

resemble the endogenous substances (such as sugars, amino acids, nucleic
acid precursors) that are the normal substrates for the particular carrier
system.

 E.g. of drugs actively transported are levodopa (for parkinsonism) and α-

methyldopa (for hypertension) at nerve endings, Iodide uptake into the
thyroid gland, reuptake of methotrexate in the gut.
ii Facilitated diffusion

 Passive facilitated diffusion involves movement down a concentration

gradient without an input of energy.

 It has many of the characteristics associated with active transport,

including being a protein carrier–mediated transport system that
shows saturability and selectivity.

 It differs from active transport, however, in that no energy input is

required beyond that necessary to maintain normal cellular function.

 In facilitated transport the movement of the transported molecule is

from regions of higher to regions of lower concentrations, so the
driving force for facilitated transport is the concentration gradient.

 This mechanism, which may be highly selective for specific

conformational structures, is necessary for transport of endogenous
compounds whose rate of transport by simple diffusion would
otherwise be too slow.

 E.g. of facilitated diffusion is transport of glucose into red blood cells.

Passive transport Active transport

Simple ATP
Diffusion Facilitated diffusion
EXTRACELLULAR
FLUID

Channel protein Solute

CYTOPLASM

(a) A channel protein

Carrier protein Solute

(b) A carrier protein

B. Endocytosis
 Endocytosis involves the cellular uptake of exogenous molecules
or complexes inside plasma membrane–derived vesicles.
 This process can be divided into two major categories:
(1) Phagocytosis or adsorptive uptake of particles that have been
bound to the membrane surface (“cellular eating”).
(2) Pinocytosis or fluid uptake, in which the particle enters the cell
as part of the fluid phase (“cellular drinking”). For example
Vitamin A, D, E, and K as well as renal tubular re-absorption of
amino acids such as glycine and the drug gentamycin
 The solute within the vesicle is released intracellularly, possibly
through lysosomal digestion of the vesicle membrane or by
intermembrane fusion.

Other ways by which drug molecules cross the cell membrane

include:
 Bulk transport: necessary for large molecules
 Ion pair transport: for highly ionized compounds
 Exocytosis: molecules leaving the cell through fusion of internal
vesicles with membrane
Phagocytosis Pinocytosis

 In phagocytosis a cell engulfs a In pinocytosis, molecules are

particle in a vacuole. taken up when extracellular
fluid is “gulped” into tiny
• The vacuole fuses with a vesicles
lysosome to digest the particle
ILLUSTRATION OF DIFFERENT TRANSPORT
MECHANISMS
ABSORPTION
 Absorption is the movement of drug from its site of administration
into the systemic circulation and the extent to which this occurs.
 For solid dosage forms, absorption first requires dissolution of the
tablet or capsule, thus liberating the drug to be absorbed into the
local circulation from which it will distribute to its sites of action.
 Except when given i.v, the drug has to cross biological membrane.
 Factors affecting drug absorption are:
1. pH
2. Aqueous solubility: Drugs given in solid form must dissolve in the
aqueous biophase before they are absorbed. For poorly water
soluble drugs (e.g. aspirin), the rate of dissolution governs the
rate of absorption. If a drug is given as water solution, it is
absorbed faster than the same given in solid form.
3. Concentration: Passive transport depends on the concentration
gradient. A drug given as concentrated solution is absorbed faster
than dilute solution.
4. Area of absorbing surface: If the area is larger, the absorption is
faster.
5. Vascularity of absorbing surface: Blood circulation removes the
drug from the site of absorption and maintains concentration
ORAL INGESTION
Absorption from the gastrointestinal (GI) tract is governed by factors such as:
1. Surface area for absorption: The epithelium of the stomach is lined with a thick
mucous layer, and its surface area is small; by contrast, the villi of the upper
intestine (duodenum) provide an extremely large surface area (~200 m2).
Accordingly, the rate of absorption of a drug from the intestine will be greater
than that from the stomach even if the drug is predominantly ionized in the
intestine and largely non-ionized in the stomach.

2. Gastric emptying: Any factor that accelerates gastric emptying will be likely to
increase the rate of drug absorption, whereas any factor that delays gastric
emptying is expected to decrease the rate of drug absorption.

3. Intestinal motility: Increased gastrointestinal motility may facilitate drug

absorption by thoroughly mixing intestinal contents and thereby bringing the
drug into more intimate contact with the mucosal surface. However, the
opposite may also occur in that an increase in motility may reduce contact time
in the upper portion of the intestine where most of drug absorption occurs.
Conversely, a decrease in gastrointestinal motility may promote absorption by
increasing contact time. Thus, the effect depends on the drug and change in
motility. Serious intestinal diseases, particularly those associated with intestinal
sloughing, can be expected to alter drug absorption dramatically.

4. Blood flow to the absorption site: Blood flow to the intestine is greater than to
the stomach, thus absorption from the intestine is favoured over the stomach.
5. The physical state of the drug (solution, suspension, or solid
dosage form): for drugs given in solid form, the rate of dissolution
may be the limiting factor in their absorption. Drugs that are
destroyed by gastric secretions or that cause gastric irritation are
sometimes administered in dosage forms with an enteric coating
that prevents dissolution in the acidic gastric contents. E.g. aspirin
is administered in enteric coats because it can cause gastric
irritation. Drugs administered in aqueous solution are absorbed
faster and more completely than tablet or suspension forms.
Suspensions of fine particles (microcrystalline) are better absorbed
than are those of larger particles.

6. Water solubility of the drug : Since most drug absorption from the
GI tract occurs by passive diffusion, absorption is favored when the
drug is in the non-ionized and more lipophilic form. Unionized lipid
soluble drugs (e.g. ethanol) are readily absorbed from GIT. Acid
drugs (aspirin, barbiturates, etc.) are predominantly unionized in
the acid gastric juice and are absorbed from the stomach, though
absorption from the stomach is slower. Basic drugs (e.g. atropine,
morphine, etc.) are largely ionized and are absorbed only from the
duodenum.

7. Presence of food in the stomach : Presence of food in the stomach

both dilutes the drug and slows gastric emptying. A drug taken with
ABSORPTION FROM THE LUNGS (PULMONARY
ABSORPTION)
 The lungs serve as a major site of administration for a
number of agents given for both local and systemic effects.

 Such drugs can be inhaled as gases (e.g., volatile anesthetics)

or as aerosols (suspended liquid droplets or solid particles).

 Access to the circulation is rapid by this route because the

lung’s surface area is large (~140 m2), thickness of the
pulmonary alveolar membranes is limited (approximately
0.2 ), and blood flow to the alveolar region is high.

 First-pass metabolism is avoided.

SUBLINGUAL /BUCCAL CAVITY
ADMINISTRATION
 A drug could be placed under the tongue (sublingual
administration) or between the cheek and gum (buccal cavity) in a
formulation that allows rapid tablet dissolution in salivary
secretions.

 The extensive network of blood vessels facilitates rapid drug

absorption.

 Venous drainage from the mouth is to the superior vena cava,

which protects highly soluble drugs like nitroglycerin which
effects are rapidly required in cases of angina.

 If taken orally, nitroglycerin would be absorbed from the

gastrointestinal tract and carried to the liver, where it is subject to
rapid metabolism and inactivation.

 If a tablet of nitroglycerin were swallowed, the accompanying

hepatic metabolism would be sufficient to prevent the appearance
of any active nitroglycerin in the systemic circulation.
ABSORPTION OF DRUGS THROUGH THE SKIN
(TRANSDERMAL ABSORPTION)
 Most drugs that have been incorporated into creams or
ointments are applied to the skin for their local effect.
 Absorption of drugs able to penetrate the intact skin is
dependent on the surface area over which they are
applied and their lipid solubility
 Unwanted effects can be produced by absorption
through the skin of highly lipid-soluble substances
(e.g., a lipid-soluble insecticide in an organic solvent).

RECTAL ADMINISTRATION
 The rectal route, though less predictable, can be used
when oral ingestion is precluded because the patient is
unconscious or when vomiting is present.
 Approximately 50% of the drug that is absorbed from
the rectum will bypass the liver, thus reducing the
hepatic first-pass effect.
PARENTERAL INJECTION
1. Intravenous:
 Ensures immediate pharmacological response.
 Problems of absorption are circumvented because the entire quantity of drug
enters the systemic circulation directly (i.e. bioavailability is complete).

2. Intramuscular and Subcutaneous

 Intramuscular and subcutaneous injections are by far the most common means of
parenteral drug administration.
 Because of the high tissue blood flow and the ability of the injected solution to
diffuse laterally, drug absorption generally is more rapid after intramuscular than
after subcutaneous injection.
 Drug absorption from intramuscular and subcutaneous sites depends on the
quantity and composition of the connective tissue, the capillary density, and the
rate of vascular perfusion (i.e. blood flow) of the area.

3. Intrathecal
 The blood–brain barrier and the blood–cerebrospinal fluid (CSF) barrier often
preclude or slow the entrance of drugs into the CNS.
 Therefore, when local and rapid effects on the meninges or cerebrospinal axis are
desired, drugs sometimes are injected directly into the spinal subarachnoid
space.
 Brain tumors may be treated by direct intraventricular drug administration.
BIOAVAILABILITY
 Bioavailability is the fraction of administered drug that reaches the
systemic circulation in a chemically unchanged form:

 If 100mg are of a drug is administered orally and 70mg of the drug is

absorbed unchanged, then bioavailability is 70%.

 Bioavailability of a drug administered IV =100%.

 Bioavailability is determined by comparing plasma levels of a drug

after a particular route of administration (after oral) with plasma levels
achieved (e.g. after IV)
 When given orally only part of the administered drug appears in the
plasma
 By plotting plasma concentrations of the drug versus time, one can
measure the surface area under the curve (AUC)

 Absolute bioavailability: Measures the availability of the active drug in

systemic circulation after non-intravenous administration (i.e., after
oral, rectal, transdermal, subcutaneous administration).
 Relative bioavailability: Measures the bioavailability of a certain drug
when compared with another formulation of the same drug, usually an
established standard, or through administration via a different route.
 When the standard consists of intravenously administered drug, this is
known as absolute bioavailability
Plasma concentration (mcg/ml)

AUC – area under the curve

F – bioavailability AUC oral
F = ------------ x 100%
AUC i.v.
(i.v. application)

(oral application)

0 5 10 15
Time (h)
BIOEQUIVALENCE

 Two related drugs are bioequivalent if they show

comparable bioavailability and similar times to
achieve peak plasma concentration.

 Two related drugs with a significant difference in

bioavailability are said to be bio-inequivalent
DRUG DISTRIBUTION
 Drug distribution refers to the movement of drug to and from the
blood and various tissues of the body (for example, fat, muscle,
and brain tissue) and the relative proportions of drug in the
tissues.

 After a drug is absorbed into the bloodstream, it rapidly circulates

through the body. And as the blood re-circulates, the drug moves
from the bloodstream into the body's tissues.

 Once absorbed, most drugs do not spread evenly throughout the

body.

 Drugs that dissolve in water (water-soluble drugs), such as the

antihypertensive drug atenolol tend to stay within the blood and
the fluid that surrounds cells (interstitial space).

 Drugs that dissolve in fat (fat-soluble drugs), such as the

anaesthetic drugs halothane and thiopental, tend to concentrate in
fatty tissues.

 Other drugs concentrate mainly in only one small part of the body
(for example, iodine concentrates mainly in the thyroid gland),
because the tissues there have a special attraction for and ability to
retain (affinity) the drug.
DISTRIBUTION INTO BODY COMPARTMENTS

 The total volume of the fluid compartments of the body into which
drugs may be distributed is approximately 40L in a 70-kg adult.

 The total body water, in which a drug can be dissolved, can be

roughly divided into three compartments:

1. Intravascular (blood plasma found within blood vessels), 3 litres

(4% BW)
2. Interstitial/ extracellular tissue (fluid surrounding cells), 9 litres
(13% BW).
3. Intracellular (fluid within cells, i.e. cytosol), 28 litres (41% BW).

 Total extracellular water is the sum of the plasma and the

interstitial water.

 Distribution is generally uneven because of differences in binding

in tissues, regional variations in pH, differences in the
permeability of cellular membranes and physical and chemical
properties of the drug.
APPARENT VOLUME OF DISTRIBUTION
 The volume into which the drug distributes is called the Apparent
Volume of distribution (Vd).
 It relates the amount of drug in the body to the concentration of
drug (C) in the blood or plasma depending on the fluid measured

Vd = Dosage/Plasma concentration

Thus 500 mg of a drug is administered to provide a plasma

concentration of

50mg/L then;

Vd = 500/50 = 10L

 Vd may vary widely depending on :

 Blood flow rate and accumulation in poorly perfused tissues (such

as fat and muscles).
 Capillary permeability
 Plasma protein and tissue protein binding
 Partition coefficient of the drug in fat
FACTORS AFFECTING DRUG
DISTRIBUTION
 Once a drug has entered the blood compartment, the rate at which it
penetrates tissues and other body fluids depends on several factors.
These include:
1. Capillary permeability:
 Determined by capillary structure and chemical nature of the drug
 Endothelial cells have slit junction (except in brain) where large part
of basement membrane is exposed due to large discontinuous
capillaries through which large proteins can pass e.g. liver and
kidneys
 Blood brain barrier: drugs have to pass through endothelial cells of
the capillaries of the CNS or be actively transported. E.g. the large
neutral amino acid carrier transports levadopa into the brain.
 Lipid soluble drugs readily penetrate into the CNS
2. Blood flow:
 Rate of blood flow to tissues and capillaries varies widely as
a result of unequal distribution of cardiac out put to the
various organs

 Blood flow to the brain, liver and kidney is greater than that
to the skeletal muscles and adipose tissue.

 Redistribution. Highly lipid soluble drugs given i.v. or by

inhalation get distributed to organs with high blood flow.
Later they get distributed to less vascularized tissues and
the drug-plasma concentrations falls.

 The greater the lipid solubility of the drug, the faster its
redistribution. Anesthetic action of thiopental is terminated
in few minutes due to redistribution. However, when the
same drug is given repeatedly or continuously over long
periods the low perfusion high capacity sites get
progressively filled up and the drug becomes longer acting.
3. Physicochemical properties of the drug
i. Partition Coefficient: The Partition coefficient (Po/w) and can be used to
determine where a drug will likely be distributed in the body.

 Any drug with a Po/w greater than 1 (diffuse through cell membranes
easily) is likely be to found throughout all three fluid compartments.

 Drugs with low Po/w values are often unable to cross and require more
time to distribute throughout the rest of the body.

ii. Size of the drug:.

 Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively
diffuse through cell membranes.

 Antibodies and other drugs range into the thousands of daltons . Drugs
>200 Da with low Po/w values cannot passively cross membranes . They
require specialized protein-based transmembrane transport systems
resulting in slower distribution

 Drugs < thousand daltons with high Po/w values simply diffuse between
the lipid molecules that make up membranes, while anything larger
requires specialized transport.

iii. Hydrophobic drugs with a uniform distribution of positive and negative

charges readily cross plasma membranes.

iv. Hydrophilic drugs have to go through slit junctions

4. Plasma and tissue protein binding

 The extent of the distribution of drugs into tissues depends on binding to plasma
proteins and tissue components.

 Most drugs found in the vascular compartment are bound reversibly with one or
more of the macromolecules in plasma (e.g plasma proteins and blood cells).

 Drugs bind to plasma proteins mainly Albumin, α1-acid glycoprotein, and

lipoproteins. Other proteins are globulins, transferrin, and ceruloplasmin.

 Acidic drugs (e.g. warfarin, digoxin and salicylic acid) bind more extensively to
albumin.

 Basic drugs (e.g . amphetamine, Propanolol, TCAs) bind to either alpha 1-acid
glycoprotein (1-AGP), or lipoproteins, or both.

 The ratio of bound to free drug in the plasma is determined by the reversible
interaction between a drug molecule and a molecule of the protein in which it binds.

 The amount of drug bound to protein depends on:

 The drug concentration
 Affinity of binding sites on the protein for the drug, and
 Number of binding sites.
 High degree of protein binding generally makes the drug long
acting, because bound fraction is not available for metabolism or
excretion, unless it is actively extracted by liver or kidney tubules.
 At low drug concentrations, the stronger the affinity between the
drug and protein, the smaller the fraction that is free.
 As drug dosage increases, protein becomes saturated and any
additional drug will remain unbound.
 Only unbound drug is pharmacologically active. The bound
fraction is not available for action.
DRUGS BOUND TO PLASMA PROTEINS
ALPHA 1-ACID
ALBUMIN G LY C O P R O T E I N

Benzodiazepines, Lidocaine
Nonsteroidal antiinflammatory Imipramine
drugs (NSAIDs e.g. aspirin)
Verapamil
Vitamin C,
Methadone
Salicylates,
Sulfonamides Prazosin
Barbiturates Quinidine
Phenylbutazone Bupivacaine
Penicillins Disopyramide
tetracyclines
Probenecid
Warfarin
Phenytoin
Valproic acid
Others (non drugs): Bilirubin,
Bile acids, Fatty Acids
TISSUE BINDING
Drugs may also accumulaate in specific organs or get bound to
specific tissue constituents, e.g:
 Adipose tissue: Drugs with extremely high lipid-water partition
coefficient e.g. thiopental, minocycline, ether, phenoxybenzamine.
These drugs dissolve in neutral fat due to high lipid solubility and
remain stored due to poor blood supply to adipose tissues.
 Bone and teeth: tetracyclines (and other divalent metal-ion
chelating agents), heavy metals (lead, strontium).
 Kidney: contains a protein, metallothionein, that has a high
affinity for metals (cadmium, lead, .and mercury), digoxin,
chloroquine, emetine.
 Eye: Chlorpromazine and other phenothiazines bind to melanin
and accumulate in the uveal tract, where they may cause
retinotoxicity.
 Lung: Most compounds that accumulate in the lung are basic
amines (e.g. antihistamines,imipramine, amphetamine)
 Liver: chloroquine, tetracyclines, emetine, digoxin, mepacrine
 Thyroid: iodine
 Skeletal muscle, heart: digoxin, emetine (binds to muscle proteins)
 Brain: Chlorpromazine, isoniazid, acetazolamide
ELIMINATION

The sum process of drug loss from the body

Elimination

Drug Metabolism
(Biotransformation) Excretion
METABOLISM (BIOTRANSFORMATION)

 Metabolism includes chemical alteration of the drugs

in the body. The mechanism to metabolize drugs is
developed to protect the body from toxins.

 In pharmacology, the term metabolism often refers

to the process of making a drug more polar and
water soluble, making it more easily excreted.

 Most hydrophilic drugs (e.g. gentamycin,

neostigmine, mannitol) are not biotransformed and
are excreted unchanged.

 The primary site for drug metabolism is the liver,

other sites are the kidney, intestine, lungs, and
plasma.
Metabolism of drugs may lead to the following:
a) Inactivation. Most drugs and their active metabolites are
converted to less active or inactive metabolites, e.g.
phenobarbital, morphine, propranolol, etc.

b) Active metabolite from an active drug. Many drugs are

converted to one or more active metabolites (e.g. diazepam
oxazepam, temazepam, nordiazepam).

c) Activation of inactive drug. Few drugs (so called prodrugs) are

inactive as such. They need conversion in the body to one or
more active metabolites (e.g. Levodopa Dopamine,
Phenacetin Acetaminophen, aspirin salicylic acid).

The prodrug may offer advantages over their active forms in

being more stable, they can have better bioavailability (e.g.
benfotiamine) or other desirable pharmacokinetic properties
or less side effects and toxicity.
 Drug metabolism reactions are carried out by enzyme
systems that evolved over time to protect the body
from exogenous chemicals.
 These enzymes can be grouped into two categories:

1. Microsomal enzymes: Present in the smooth

endoplasmic reticulum of the liver, kidney and GIT e.g.
glucuronyl transferase, dehydrogenase , hydroxylase and
cytochrome P450.
2. Non microsomal enzymes: Present in the cytoplasm,
mitochondria of different organs. e.g. esterases, amidase,
hydrolase.

 Biotransformation reactions can be classified into two

phases: I (non synthetic) and II (synthetic, conjugation).
PHASE 1: NON SYNTHETIC
REACTIONS
 The Phase I reactions most frequently involved in drug metabolism are
catalyzed by the cytochrome P-450 system (also called microsomal mixed
function oxidase).
 These reactions converts parent compound into a more polar (=hydrophilic)
metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -
COOH, etc.). Phase 1 reactions are majorly oxidation, reduction, and
hydrolysis.

a) Oxidation: it is the most important drug metabolizing reaction. Various

oxidation reactions are hydroxylation; oxygenation at C-, N- or S-atoms; N
or 0-dealkylation, oxidative deamination, etc.
 Oxidative reactions are mostly carried out by a group of monooxygenases
in the liver, which in the final step involve cytochrome P450 reductase and
O2.

b). Reduction: This reaction is conversed of oxidation and involves CYP450

enzymes working in the opposite direction. Drugs, primarily reduced, are
chloramphenicol, levodopa, halothane.
DOPA-decarboxylase
Levodopa (DOPA) Dopamine
PHASE 1: NON SYNTHETIC
REACTIONS
c) Hydrolysis: This is cleavage of a drug molecule by taking up a
molecule of water.Esterase
Ester + H20 Acid + Alcohol
 Similarly amides and polypeptides are hydrolyzed by amidase
and peptidases. Hydrolysis occurs in the liver, intestines,
plasma, and other tissues. Examples are choline esters,
procaine, lidocaine, pethidine, oxytocin.

d) Cyclization: this is formation of a ring structure from a

straight chain compound, e.g. proguanil.

e) Decyclization: is opening up of a ring structure of the cyclic

molecule, e.g. phenytoin, barbiturates.
PHASE 2: SYNTHETIC (CONJUGATION)
REACTION
 These involve conjugation of the drug or its phase I metabolite with an
endogenous substrate to form a polar highly ionized organic acid, which is
easily excreted in the urine or bile. Conjugation reactions have high energy
requirements.

(1) Glucuronide conjugation is the most important synthetic reaction.

Compounds with a hydroxyl or carboxylic acid group are easily conjugated with
glucuronic acid, which is derived from glucose, e.g. chloramphenicol, aspirin,
morphine, metronidazole, bilirubin, thyroxine. Drug glucuronides, excreted in
bile, can be hydrolyzed in the gut by bacteria, producing beta-glucuronidase.

(2) Acetylation. Compounds having amino or hydrazine residues are conjugated

with the help of acetyl CoA, e.g. sulfonamides, isoniazid. Multiple genes control
the acetyl transferases and rate of acetylation shows genetic polymorphism
(slow and fast acetylators).

(3) Sulfate conjugation. The phenolic compounds and steroids are sulfated by
sulfokinases, e.g. chloramphenicol, adrenal, and sex steroids.

(4) Methylation . The amines and phenols can be methylated. Methionine and
cysteine act as methyl donors e.g methylation of epinephrine to metanephrine.
(5) Ribonucleoside/nucleotide synthesis is important for the
activation of many purine and pyrimidine antimetabolites used in
cancer chemotherapy, e.g. Xeloda®.

(6) Only a few drugs are metabolized by enzymes of

intermediary metabolism. Examples:
• Alcohol by dehydrogenases
• Allopurinol by xanthine oxidase
• Succinylcholine and procaine by plasma cholinesterase
• Adrenaline by monoamine oxidase (MAO)
CYTOCHROME P450
ENZYMES
 Primary phase I enzyme system involved in the
oxidative metabolism of drugs and other
chemicals.
 It is located in the endoplasmic reticulum of
hepatocytes. They are also expressed in the
intestine (responsible for first pass metabolism
at this site) and in the kidney.
 They act on structurally unrelated drugs and
metabolize the widest range of drugs.
 Consists of > 50 isoforms.
 In different people and different populations,
activity of CYP oxidases differs.
 CYP3A4 is thought to be the most predominant
CYP isoform involved in human drug metabolism.
 CYP3A4 may account for more than 50% of all
CYP-mediated drug oxidation reactions
Substrates: Tolbutamide Midazolam Dextro-
Nifedipine Caffeine Chlor-
Mephenytoin Warfarin metorphan
Cumarins Erythromycin Theophylline zoxazone
Omeprazole Phenytoin Debrisoquine
Cyclosporine Tacrine

CYP3A4/5 CYP1A2
CYP2C19
CYP2C8/9/18 CYP2E1 CYP2D6
CYP2B6 CYP2A6
(30–50%) ~15% <5%
CYP1A1
<5% <5% ~20% ~10%

Inhibitors:
Methoxsalen Fluconazole Sulphaphenazole Ketoconazole Furafylline Tetrahydro- Quinidine
Gestodene Fluvoxamine furane

Inducers:
Phenobarbital Omeprazole Ethanol
Pheno- Phenobarbital Phenobarbital
Rifampicin Rifampicin Rifampicin Nicotine Isoniazid
barbital
Dexamethasone
Carbamazepine
The two phases of drug metabolism
Synthetic (conjugation) reactions
FIRST PASS METABOLISM
This refers to metabolism of a drug during its passage from the site of
absorption into systemic circulation. All orally administered drugs are
exposed to drug metabolism in the intestinal wall and liver in different
extent.

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver

to
Dose systemic
circulation
EXCRETION
EXCRETION
 Excretion is the passage out of systematically absorbed drugs.
 Drugs and their metabolites are excreted in:
• urine (through the kidney)
• bile and faeces
• exhaled air
• saliva and sweat
• Milk
• Skin

 The kidney is responsible for excreting all water soluble

substances.

Glomerular filtration. Glomerular capillaries have large pores. All non protein
bound drugs (lipid soluble or insoluble) presented to the glomerulus are
filtrated. Glomerular filtration of drugs depends on their plasma protein binding
and renal blood flow. Small nonionic drugs pass more readily. Glomerular
filtration rate (g.f.r.) declines progressively after the age of 50 and is low in
renal failure.

Tubular reabsorption. Drugs are reabsorbed into the blood stream from the
nephron tubule. Small nonionic drugs diffuse readily. Lipid soluble drugs
filtrated at the glomerulus diffuse back into the body across the tubules
because 99% of glomerular filtrate is reabsorbed, but non lipid soluble and
•aminoglycosides
•beta-lactams
•sulfonamides
•quinolones
•nitrofurans
•polymyxins
macrolides
lincosamines
rifampicin
tetracyclines (p.o.)
General inhalation
anaesthetics
Potassium iodide
Broncho-
antiseptic oils
Alcohol
•sulfonamides
•barbiturates
•Alcohol
•reserpine
•Coffeinum
(Caffeine)
Rauwolfia serpentina
(Reserpine: India)
Saliva excretion

oleandomycin
spiramycin
phenytoin
zalcitabine
verapamil
Morphine
10% stomach excretion)
morphine pKb: 7.9
stomach pH: 1–2
plasma pH: 7.36

Poppy
KINETICS OF ELIMINATION
(elimination = metabolism +

excretion)
Clearance (Cl) of a drug is the volume of plasma from
which the drug is removed per unit time

 It refers to the volume of plasma that would be

completely cleared of drug (per unit time) if all drug
being excreted /metabolized were removed from that
volume (and the remaining fluid in the body retained the
original concentration of the drug).

 Clearance is measured in litres per hour

Cl = Elimination rate/drug concentration or,

Cl = k. Vd
Where k = elimination rate constant
Vd = apparent volume of distribution
FIRST ORDER (EXPONENTIAL)
KINETICS
 The first order kinetics is the elimination of a constant fraction of
drug quantity present per unit time.

 The rate of elimination of a drug is directly proportional to plasma

drug concentration. E.g. 1% of the drug quantity is eliminated per
minute.

 The time course of the decrease of the drug concentration in the

plasma can be described by an exponential equation of the form:
C = C(0) e –λt

Where:
C = drug concentration
C(0) = extrapolated initial drug concentration
λ = elimination rate constant
t = time
 Although the amount of drug eliminated in a
first-order process changes with concentration,
the fraction of a drug eliminated remains
constant.

Rate of elimination proportional to Cp.

Cp decays exponentially with time

The serum level curve observed from a drug eliminated by a first order
process:
A plot of this same data using a log scale on the y-axis results in a straight
line.
ZERO ORDER (LINEAR) KINETICS.
 Zero order elimination implies that elimination is constant
regardless of drug concentration in the plasma. E.g. 1.2 mg
are eliminated every hour, independently of the drug
concentration in the body.
 The drugs are removed at a constant rate which is
independent of plasma concentration.
 Zero order elimination is rather rare, mostly occurring when
the elimination system is saturated.
 E.g of drugs that follow the zero order elimination are ethanol
, phenytoin, theophylline, salicylates, and warfarin

The blood alcohol

Concentration falls
linearly and the
rate of fall does
not vary with
dose.
CLINICAL IMPLICATIONS
 In clinical pharmacology, first order kinetics are considered as a
linear process, because the rate of elimination is proportional to
the drug concentration. This implies that the higher the drug
concentration, the higher its elimination rate. In other words, the
elimination processes are not saturated and can adapt to the needs
of the body to reduce accumulation of the drug.

 95% of the drugs in use at the therapeutic concentrations are

eliminated by first order elimination kinetics

 A few substances are eliminated by zero-order elimination kinetics,

because their elimination process is saturated. Examples are
ethanol, phenytoin, salicylates, fluoxetin, omeprazole, cisplatin.

 Because in a saturated process, the elimination rate is no longer

proportional to the drug concentration but decreasing at higher
concentrations, zero-order kinetics are also called non-linear
kinetics in clinical pharmacology.
HALF LIFE

 Plasma half life (t1/2) is the time it takes for the plasma concentration
of a drug to be reduced by 50%.
 By definition, plasma concentration of a drug is halved after one
elimination half life. Therefore, in each succeeding half-life, less drug
is eliminated.
 After one half-life, the amount of the drug remaining in the body is
50%, after two half-lives, 25%, etc.
 After 4 half-lives, the amount of drug (6.25%) is considered to be
negligible regarding its therapeutic effects.
 The half-life of a drug depends on its clearance and volume of
distribution

Clinical implications:
 Half-life determines the length of the drug effect.
 Indicated whether accumulation of the drug will occur under a
multiple dosing regimen
 Its essential to decide the appropriate dosing interval.
From the peak plasma concentration the drug is vir-
tually eliminated from the plasma in 5 t1/2 periods:

(1) (2) (3) (4) (5)

END