DRUG

BIOTRANSFORMATION
(METABOLISM)

Dr.Taita Towett Lee.,M.P.S.,Bpharm-MUST.

Objectives
 By the end of this session, students should be able to;
Define drug metabolism,
Understand where drug metabolism takes place,
Describe the drug metabolizing systems,
With examples, discuss the phases of drug metabolism,
Discuss the factors affecting drug metabolism.

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Introduction
 Drug metabolism (biotransformation) is the process by
which the body changes a drug from its dosage form to a
more water-soluble form that can then be excreted.
 Other drugs are converted to active metabolites, which are
capable of exerting their own pharmacologic action. Active
metabolites may undergo further metabolism or may be
excreted from the body unchanged.
 Some drugs can be administered as inactive drugs, called
prodrugs, which don’t become active until they’re
metabolized.

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Where does drug metabolism happen?
 The majority of drugs are metabolized by enzymes in the
liver however, metabolism can also occur in other tissue
sites (due to the presence of enzymes): Lungs, GIT
(Intestinal mucosa), Skin, Placenta, Kidney, adrenals,
blood the plasma, kidneys, and membranes of the
intestines.
 Subcellular locations: smooth endoplasmic reticulum (e.g.
cP450-group of heme proteins), mitochondria, cytosol,
lysozymes, nuclear envelope, plasma membrane .

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Types of Drug Metabolizing Systems
i. Enzymes
Substrate Specific Enzymes can degrade drug analogues of
normal body substances
 Exogenous analogues – readily degraded by the body using
specific enzymes e.g. DOPA – oxidase
• Acetylcholine (endogenous or exogenous) acted upon by
acetylcholinesterase , MAO (monoamine oxidase) and COMT
(catecholamine-o-methyl-transferase) –degrade norepinephrine
and other catecholamines.

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ii. Broad Substrate Specific Enzymes degrade a broad
spectrum of substrates, do not degrade specific drug analogues
of normal physiologic constituent e.g. broad plasma
pseudocholinesterase -degrades non-specific esters such as
succinylcholine(musclerelaxant), anesthetic: lidocaine (amide) and
procaine (ester).

iii. Non-enzymatic Processes e.g. Hydrolysis.

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Phases of Drug Biotransformation

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1. Phase I (nonsynthetic)
 These reactions generally precede phase II reactions and
include oxidative, reductive and hydrolytic reactions.
 Phase I reactions convert lipophilic molecules into more
polar molecules by introducing or unmasking a polar
functional group, such as –OH or –NH2. Thus, phase I
reactions are also called functionalizing reactions.
 Phase I metabolism may increase, decrease, or leave
unaltered the drug’s pharmacologic activity.

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 Phase I reactions utilizing the P450 system
 The Phase I reactions most frequently involved in drug
metabolism are catalyzed by the cytochrome P450 system
(microsomal mixed-function oxidases):
Drug + O2+ NADPH + H+→ Drug modified+ H2O + NADP+
 The oxidation proceeds by the drug binding to the oxidized form
of cytochrome P450, and then oxygen is introduced through
a reductive step, coupled to NADPH:cytochrome P450 oxido
-reductase.

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 The P450 system is important for the metabolism of many
endogenous compounds (such as steroids, lipids, etc.) and for
the biotransformation of exogenous substances (xenobiotics).
 Cytochrome P450, designated as CYP, is a superfamily of heme
containing isozymes that are located in most cells but are
primarily found in the liver and GI tract.
 The family name is indicated by CYP added to an arabic number,
followed by a capital letter for the subfamily e.g. CYP3A.
Another number is added to indicate the specific isozyme, as in
CYP3A4.

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 The isozymes responsible for the metabolism vast majority
are CYP3A4/5, CYP2D6, CYP2C8/9, and CYP1A2.
 Considerable amounts of CYP3A4 are found in intestinal
mucosa, accounting for the first-pass metabolism of
drugs such as chlorpromazine and clonazepam.

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Genetic variability of CYP 450
 P450 enzymes exhibit considerable genetic variability among
individuals and racial groups.
 Variations in P450 activity may alter a drug’s efficacy and the risk
of adverse events.
 CYP2D6, in particular, has been shown to exhibit genetic
polymorphism.
 CYP2D6 mutations result in very low capacities to metabolize
substrates. Some individuals, for example, obtain no benefit
from the opioid analgesic codeine, because they lack the
CYP2D6 enzyme that O-demethylates and activates the drug
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 Similar polymorphisms have been characterized for the CYP2C
subfamily of isozymes.
 Patients who are poor CYP2C19 metabolizers have a higher
incidence of cardiovascular events (e.g. stroke or myocardial
infarction) when taking clopidogrel. This agent is a prodrug,
and CYP2C19 activation is required to convert it to its
(active) metabolite.

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CYP 450 Inducers
 The CYP450–dependent enzymes are an important target
for pharmacokinetic drug interactions. One such
interaction is the induction of selected CYP isozymes.
 Xenobiotics may induce the activity of these enzymes by
inducing the expression of the genes encoding the enzyme or
by stabilizing the enzymes.
 Certain drugs e.g. phenobarbital, rifampin, and carbamazepine
are capable of increasing the synthesis of one or more CYP
isozymes.
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 This results in increased biotransformation of drugs and can
lead to significant decreases in plasma concentrations of
drugs metabolized by these CYP isozymes, as measured
by AUC (a measure of drug exposure), with concurrent
loss of pharmacologic effect.
 Rifampin, an antituberculosis drug, significantly decreases the
plasma concentrations HIV protease inhibitors, thereby
diminishing their ability to suppress HIV virion maturation.

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 Consequences of increased drug metabolism include:
1. Decreased plasma drug concentrations.
2. Decreased drug activity if the metabolite is inactive.
3. Increased drug activity if the metabolite is active.
4. Decreased therapeutic drug effect.

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CYP 450 Inhibitors
 Inhibition of CYP isozyme activity is an important source of drug
interactions that lead to serious adverse events.
 The most common form of inhibition is through competition for
the same isozyme. Some drugs, however, are capable of inhibiting
reactions for which they are not substrates leading to drug
interactions.
 Numerous drugs have been shown to inhibit one or more of the
CYP-dependent biotransformation pathways of warfarin.
 For example, omeprazole is a potent inhibitor of three of the
CYP isozymes responsible for warfarin metabolism

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 If the two drugs are taken together, plasma concentrations of
warfarin increase, which leads to greater inhibition of
coagulation and risk of hemorrhage and other serious bleeding
reactions.
 Cimetidine blocks the metabolism of theophylline,
clozapine, and warfarin.
 Natural substances may also inhibit drug metabolism e.g.
because grapefruit and its juice inhibits CYP3A4, drugs such
as nifedipine, clarithromycin, and simvastatin, which are
metabolized by this system, persist in greater amounts in the
systemic circulation, leading to higher blood levels and the
potential to increase the drugs therapeutic and toxic effects.
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Phase I reactions not involving the P450 system
 These include:
Amine oxidation (e.g. oxidation of catecholamines or
histamine).
Alcohol dehydrogenation (e.g. ethanol oxidation).
Esterases (e.g. metabolism of pravastatinin liver).
Hydrolysis (e.g. of procaine).

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Phase II drug biotransformation reactions.
 They are also known as synthetic reactions.
 Occurs mostly in cytosol and a few in the microsome.
 Phase II reactions results in conjugation products.
 Reactive sites(e.g. hydoxyl, thiol, carboxylic acid or amino groups)
on the drug molecule can combine with endogenous metabolic
products such as glucuronic acid, sulfate, methyl groups or acetate
to form conjugated products.
 Gives products that are generally water soluble and easily
excreted.
 Because endogenous substrates originate in the diet, nutrition plays
a critical role in the regulation of drug conjugation.
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 Conjugated products are almost always pharmacologically
inactive in contrast to phase one products which may remain
pharmacologically active & in some cases be as or more active
than a parent drug.
 Glucuronidation is the most common metabolic reaction
followed by sulfate conjugation.
 Enzymes catalysing phase II reactions include:-
glucuronyl transferase ( glucuronide conjugation),
sulfotransferase( sulfacte conjugation, transacyclases( amino
acid conjugation), acetylases, ethylases, methylases & glutathione
transferase. These enzymes are present in numerous tissues &
some in plasma & sub cellular locations.
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 Phase II reactions
Type of Transferase Types of Examples
Endogenous
Conjugation (Location) Substrates
Reactant

Glycine Acyl-CoA Acyl-CoA Salicylic acid,

Glycine glycinetransferase derivatives of benzoic acid,
conjugation (mitochondria) carboxylic acids nicotinic acid,
deoxycholic acid

UDP glucuronic UDP glucuronosyl- Phenols, alcohols, morphine,

acid transferase carboxylic acids, acetaminophen,
Glucuronidation (microsomes) hydroxylamines, diazepam,
sulfonamides sulfathiazole,
meprobamate,
digitoxin, digoxin
Acetylation Acetyl-CoA N-Acetyltransferase Amines Sulfonamides,
(cytosol) isoniazid,
clonazepam,
dapsone, mescaline
Type of Endogenous Transferase Types of Examples
Conjugation Reactant (Location) Substrates

Glutathione Glutathione (GSH) GSH-S-transferase Epoxides, arene Acetminphen,

conjugation (cytosol, oxides, nitro groups, ethacrynic acid,
microsomes hydroxylamines bromobenzene

Methylation S-Adenosyl- Transmethylases Catecholamines, Dopamine,

methionine (cytosol) phenols, amines epinephrine,
pyridine, histamine

Sulfation Phosphoadenosyl Sulfotransferase Phenols, alcohols, Estrone, aniline,

phosphosulfate (cytosol) aromatic amines phenol,
acetaminophen,
methyldopa

Water conjugation Water Epoxide hydrolase Arene oxides, cis- Benzopyrene 7,8-
(microsomes) disubstituted and epoxide,
monosubstituted carbamazepine
oxiranes epoxide
Factors affecting biotransformation
1. Age
 Differences in drug metabolic rate in different age groups is mainly
due to variations in enzyme content, enzyme activity and
hemodynamics.
 In neonates, the microsomal enzyme system is not fully developed
and many drugs are biotransformed slowly in comparison to
adults.
 In the elderly, the liver size is reduced, the microsomal enzyme
activity is decreases and hepatic blood flow also declines as a
result of reduced cardiac output all of which contribute to
decreased metabolism of drugs.
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2. Sex:
 Sex related differences in rate of drug metabolism can be
attributed to regulation of such processes by sex hormones since
variations among males and females are generally observed
following puberty.
 Women metabolize benzodiazepines and ethanol slowly than men.

3. Diet & Environmental Factors:

 Charcoal-broiled foods and cruciferous vegetables (e.g. cabbage)
are known to induce CYP1A enzymes, whereas grapefruit juice is
known to inhibit the CYP3A metabolism of co-administered drug
substrates.
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 Cigarette smokers metabolize some drugs more rapidly than
nonsmokers because of enzyme induction. Industrial workers
exposed to some pesticides metabolize certain drugs more
rapidly than nonexposed individuals.

4. Disease states:
 As the liver is the primary site for metabolism of most drugs, all
pathological conditions associated with it result in enhanced
halflives of almost all drugs. Biotransformations which occur in
the kidney are impaired by renal disease.

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5. Interactions between Drugs & Endogenous
Compounds:
 some drugs require conjugation with endogenous substrates e.g.
glutathione, glucuronic acid, or sulfate for their inactivation.
 Consequently, different drugs may compete for the same
endogenous substrates, and the faster-reacting drug may
effectively deplete endogenous substrate levels and impair the
metabolism of the slower-reacting drug. If the latter has a steep
dose-response curve or a narrow margin of safety, potentiation
of its pharmacologic and toxic effects may result.

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7. Species difference:
 Screening of new therapeutic molecules to ascertain their activity
and toxicity requires study in several laboratory animal species.
The differences in drug response due to species differences are
taken into account while extrapolating the data to man.
 In phase I reactions, both quantitative and qualitative variations in
the enzymes and their activity have been observed e.g.
metabolism of ephedrine in man is mainly by oxidative
deamination whereas in rats, oxidative deamination is the major
route.
 Variations in phase II reactions are mainly qualitative
characterized by presence or absence of specific conjugation
enzymes. 29
7. Other drug administration:
 Induction or inhibition of metabolizing enzymes of one drug
by another drug will increase or decrease it’s rate of
metabolism respectively.

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THE END

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