Metabolism

Pharmacokinetics
Metabolism
Dr. S. Parasuraman
Associate Professor, Faculty of Pharmacy,
AIMST University, Malaysia.

Academic session: Mar. - Jul. 2022 (FoP) 2
Pharmacokinetics - biotransformation
• Metabolism (biotransformation):
• Biotransformation means chemical alteration of the
drug in the body. It is needed to render nonpolar (lipid-
soluble) compounds polar (lipidinsoluble) so that they
are not reabsorbed in the renal tubules and are excreted.

• The primary site for drug metabolism is liver; others
are—kidney, intestine, lungs and plasma.

• Biotransformation of drugs may lead to the following.
• Inactivation: Most drugs and their active metabolites are
rendered inactive or less active,. e.g. ibuprofen,
paracetamol
• Active metabolite from an active drug: Many drugs have
been found to be partially converted to one or more
active metabolite. e.g. morphine  Morphine-6-
glucuronide, Diazepam  Desmethyl-diazepam, Codeine
 Morphine.
• Activation of inactive drug (prodrug): Few drugs are
inactive as such and need conversion in the body to one
or more active metabolites. e.g. Levodopa  Dopamine,
Bacampicillin  Ampicillin

Biotransformation reactions
• Nonsynthetic / Phase – l / Functionalization reactions: a
functional group (-OH, -COOH, -CHO, -NH2 , -SH) is
or exposed-metabolite may be active or
generated
inactive.
• Synthetic/ Conjugation/ Phase II reactions: an
endogenous radical is conjugated to the drug-metabolite
is mostly inactive; except few drugs. e.g. glucuronide
conjugate.
• Certain drugs already have functional groups and are
directly conjugated, while others undergo a phase I
reaction first followed by a phase II reaction.

Biotransformation reactions - Nonsynthetic
reactions
• Oxidation: This
oxygen/negatively
reaction involves
charged radical or
addition of
removal of
hydrogen/positively charged radical. Oxidations are the
most important drug metabolizing reactions.
• Various oxidation reactions are: hydroxylation;
oxygenation at C, N or S atoms; N or O-dealkylation,
oxidative deamination, etc.
• Oxidative reactions are mostly carried out by a group of
monooxygenases in the liver, which in the final step
involve a cytochrome P-450 haemoprotein, NADPH,
cytochrome P-450 reductase and molecular O2.

reactions
• Oxidation:
• Role of cytochrome P-450 in drug metabolism:
• Cytochrome P450 (CYP) is a hemeprotein that plays a key
role in the metabolism of drugs and other xenobiotics.
• Cytochrome P450 pathways are classified by similar gene
sequences; they are assigned a family number (e.g.,
CYP1, CYP2) and a subfamily letter (e.g., CYP1A, CYP2D)
and are then differentiated by a number for the isoform
or individual enzyme (e.g., CYP1A1, CYP2D6).
• Cytochrome P450 enzymes can be inhibited or induced
by drugs, resulting in clinically significant drug-drug
interactions that can cause unanticipated ADRs.

reactions
• Oxidation:
• CYP3A4/5 Carryout biotransformation of largest number
(nearly 50%) of drugs.
• CYP2D6 This is the next most important CYP isoform
which metabolizes nearly 20% drugs including TCA, SSRIs,
antiarrhythmics, codeine, metoprolol.
• CYP2C8/9 Important in the biotransformation of >15
commonly used drugs including phenytoin,
carbamazepine, warfarin which are narrow safety margin
drugs.

reactions
Metabolizes > 12 frequently used drugs
omeprazole, lansoprazole, phenytoin,
• Oxidation:
• CYP2C19
including
diazepam.
• CYP1A1/2 though this subfamily participates in the
Metabolism of only few drugs like theophylline, caffeine,
paracetamol, carbamazepine.
• CYP2E1 catalyses oxidation of alcohol, holothane, and
formation of minor metabolites of few drugs, notably the
hepatotoxic N-acetyl benzoquinoneimine from
paracetamol.

reactions
• Reduction: This reaction is the converse of oxidation and
involves cytochrome P-450 enzymes working in the
opposite direction.
• Hydrolysis: This is cleavage of drug molecule by taking up
a molecule of water.
• Cyclization: This is formation of ring structure from a
straight chain compound, e.g. cycloguanil from proguanil.

reactions
• Decyclization: This implies opening up of ring structure
of the cyclic drug molecule, such as barbiturates,
phenytoin. This is generally a minor pathway.

Biotransformation reactions - Synthetic
reactions
• Glucuronide conjugation: This is the most important
synthetic reaction carriedout by a group of UDP-
glucuronosyl transferases (UGTs). Glucuronidation
increases the molecular weight of the drug which favours
its excretion in bile. Eg.: chloramphenicol, aspirin,
paracetamol, diazepam, morphine, metronidazole.
• Acetylation: Compounds having amino or hydrazine
residues are conjugated with the help of acetyl
coenzyme-A. Eg.: sulfonamides, isoniazid, PAS, dapsone
• Methylation: The amines and phenols can be methylated
by methyl transferases (MT). Eg.: adrenaline, histamine

Biotransformation reactions - Synthetic
reactions
• Sulfate conjugation: The phenolic compounds and
steroids are sulfated by sulfotransferases. Eg.:
chloramphenicol, methyldopa.
• Glycine conjugation: Drugs having carboxylic acid group
are conjugated with glycine, but this is not a major
pathway of metabolism. Eg.: Salicylates, nicotinic acid.
• Glutathione conjugation: The amines and phenols can be
methylated by methyl transferases (MT). Eg.: adrenaline,
histamine.
• Ribonucleoside/nucleotide synthesis: This pathway is
important for the activation of many purine and
pyrimidine antimetabolites

Biotransformation reactions
Most drugs are metabolized by multiple pathways,
simultaneously or sequentially as illustrated

Role of microsomal/ nonmicrosomal enzymes
in drug metabolism
• Microsomal enzymes are located on smooth endoplasmic
reticulum, primarily in liver, also in kidney, intestinal
mucosa and lungs. They catalyse most of the oxidations,
reductions, hydrolysis and glucuronide conjugation.
• Nonmicrosomal enzymes are present in the cytoplasm
and mitochondria of hepatic cells as well as in other
tissues including plasma. The esterases, amidases, some
flavoprotein oxidases and most conjugases are
nonmicrosomal.

Inhibition of Drug Metabolism
• Azole antifungal drugs, macrolide antibiotics and some
other drugs bind to the heme iron in CYP450 and inhibit
the metabolism of many drugs, as well as some
endogenous substances like steroids, bilirubin.

Microsomal Enzyme Induction
• Many drugs, insecticides and carcinogens interact with
DNA and increase the synthesis of microsomal enzyme
protein, especially cytochrome P-450 and UGTs. As a
result the rate of metabolism of inducing drug itself
and/or some other coadministered drugs is accelerated.

Metabolism

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