BIOPHARMACEUTICS AND PHARMACOKINETICS

Name: ________________________ Date: __________________

Section: _______________________ Score: _________________

Exercise No. 5
METABOLISM

Drug metabolism refers solely to the chemical biotransformation of a drug by the

biological environment. It is often termed detoxification, which indicates one of the main
functions of metabolism, namely, the formation of more polar and water-soluble compounds
resulting in reduction of their pharmacological activity and more rapid excretion from the body.
Drug metabolism is very complex. Usually drug metabolites are more water-soluble than
the parent structure because the derivatives contain more functional groups, or they are
conjugated with hydrophilic substances. The principal site of drug metabolism is the liver; less
important are the kidney, muscle tissue and gut wall. Metabolizing enzymes occur in the
soluble, the mitochondrial, or the microsomal fractions. However, metabolism can also take
place in the bloodstream to some extent because some enzymes produced by the cell spill over
into the extracellular fluid. Alteration of the enzyme system may predispose a person to drug-
drug interaction.

1. Differentiate Phase 1 metabolism and Phase 2 metabolism

- phase I metabolism converts a parent drug to polar active metabolites while phase II
metabolism converts a parent drug to polar inactive metabolites.
- I: Yields a polar, water-soluble, metabolite that is often still active. Many of the products
in this phase can also become substrates for phase II. Phase II: Yields a large polar
metabolite by adding endogenous hydrophilic groups to form water-soluble inactive
compounds that can be excreted by the body

2. Complete the table given below. Provide 3 examples of drugs that undergo the
metabolic pathway given.
Phase 1 Metabolism
Metabolic pathway Description Example of drug Therapeutic
classification
Oxidation (also called cellular -hydroxylation of increase synaptic
respiration) is a cellular amphetamine to 4- concentrations of
process through which hydroxyamphetamine monoamine
organisms use oxygen to and norephedrine. neurotransmitters,
break down food thereby indirectly
molecules, which are - Midazolam enhancing
organic compounds such noradrenergic,
as glucose, in order to - Ethoxyresorufin dopaminergic
extract chemical energy for neurotransmission
cell processes in the CNS.

- benzodiazepines :
acts on glycine
receptors and
 BIOPHARMACEUTICS AND PHARMACOKINETICS

produces a
muscle-relaxing
effect.

- periportal
hepatotoxicant
Reduction energy in metabolism often
flows in terms of electrons.
If electrons are lost, this is
called oxidation. If
electrons are gained, this is
called reduction.
Hydrolysis Hydrolysis is a process
whereby a compound is
broken down into simpler
compounds, and is
accompanied by the
chemical incorporation of
water. Almost all tissues
contain enzymes that
catalyze hydrolysis, but the
highest concentrations are
found in the liver.

Phase 2 Metabolism
Metabolic Enzyme Cofactor Example of Therapeutic
pathway substrate classification
Glucoronidation uridine 5'-diphosphate uridine anti-inflammatory anticonvulsants
(UDP) diphosphate- arylacetic acids and
UDP- glucuronic acid.6 aliphatic acids such
glucuronosyltransferases as valproic acid

Sulfation Sulfotransferases PAPS sulfation

reactions in
substrate eukaryotes
..synthesis of with
sulfonated implications for
glycosaminoglycans, the build-up of
such as heparin, extracellular
heparan sulfate, matrices,
chondroitin sulfate, retroviral
and dermatan infection,
sulfate. protein
modification,
and steroid
metabolism.
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Methylation bacterial radical SAM S- activated one- intermediate

enzymes RlmN and Cfr Adenosylmethionine carbon donor S- in the
(AdoMet) adenosylmethionine metabolic
(SAM) pathway of
methionine.
- to treat
depression
anti
depressant
Acetylation Histone Acetyl coenzyme A acetyl-CoA carboxylases
acetyltransferases (acetyl-CoA) (ACCs) have
(HATs) crucial roles in
fatty acid
metabolism in
humans and
most other
living
organisms
Glutathione γ-glutamyltransferase Selenium. nucleophilic attacks Detoxification :
conj (GGT; also known as γ- at electron-deficient peptides
glutamyltranspeptidase) ( carbon atoms, but
attack of a nitrogen
atom (e.g., in an
aromatic nitroso
group), a sulfur atom
(in thiols), or an
oxygen (in
hydroperoxides) is
also documented.
Glycine conj glycine N- benzoyl-coenzyme salicylate [1], dietary
participates in
acyltransferase A (CoA):glycine polyphenols and the processing
acyltransferase, medium-chain fatty of motor and
catalyzes the acids (MCFAs) sensory
condensation of information that
permits
benzoate and
movement,
glycine to form vision, and
hippurate. audition
Glutamine conj glutathione S- Most known cases Wound healing
transferases (GSTs pyridoxal of glutathione and recovery
phosphate: FAD, conjugation are from illness.
Iron, FMN, Sulfur, nucleophilic attacks When the body
and Iron-sulfur at electron-deficient is stressed
carbon atoms, but (from injuries,
attack of a nitrogen infections,
atom (e.g., in an burns, trauma,
aromatic nitroso or surgical
group), a sulfur atom procedures), it
(in thiols), or an releases the
oxygen (in hormone
 BIOPHARMACEUTICS AND PHARMACOKINETICS

hydroperoxides) is cortisol into the

also documented. bloodstream.

3. In a tabulated form, give the different significant CYP isoforms and their substrates.

CYP isoform Substrate

planar compounds with fused aromatic rings
CYP1A1 including endogenous substrates such as
estrogen and bilirubin as well as exogenous
xenobiotics.
ropranolol, clozapine, guanabenz, flutamide,
CYP1A2 imatinib, thalidomide, carbamazepine,
lidocaine, theophylline, tacrine, tizanidine,
zolpidem, riluzole, zileuton, and leflunomide.
CYP3A4
Inhibitors, Inducers. Benzodiazepinesa.
Budesonide Calcium Channel Blockersb.
Carbamazepine Corticosteroids Etoposide
Immunosuppressivesc

CYP2D6, a
CYP 450

4. Give the significance of the following Phase II metabolism:

a. Glucoronidation

b. Acetylation

c. Glutathione conjugation

d. Glycine conjugation

e. Glutamine conjugation
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f. Methylation

5. What is enzyme induction? Enzyme inhibition? Give the important effects the two.

6. Give six examples of an enzyme inducer and inhibitor with their therapeutic actions

Example Therapeutic action

Enzyme inducer

Enzyme inhibitor

7. What is Genetic polymorphism? Why is it important in drug dosing?

8. Define the following

a. Allele

b. Genome

c. Genotype

d. Haptens

e. Haplotype

f. Promoter

g. Phenotype
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9. What is first pass effect? Explain the two types of circulation involved in the metabolism
of the drug product. Give 3 examples of drug that undergoes first pass effect and their