STRUCTURALLY

ACTIVE METABOLISM
PREPARED BY: JAWAIRIA NAUREEN
CONTENTS:

Definition & Importance

Drug Metabolism Phases (Phase I & II Reactions)
Enzymes Involved (CYP450 System, Transferases, Oxidases)
Factors Affecting Drug Metabolism
METABOLISM:
Metabolism is an essential pharmacokinetic process, which converts lipid
soluble and non-polar compounds to water soluble and polar compounds so
that they are excreted by various processes.
It also includes the conversion of pro drugs into active compounds.
primary sites of metabolism include: Liver (major site), Other organs:
intestine, placenta.
Impact on Drug Clearance & Toxicity:
Affects drug elimination and metabolite-induced toxicity
Determines pharmacokinetic properties (e.g., half-life)
Crucial for drug development

drug enzymes metabolite

IMPORTANCE OF DRUG
METABOLISM:
Drug metabolism is needed to convert non-polar lipophilic compounds
which the body can't excrete into more polar hydrophilic compounds which
the body can excrete in short period of time.
Because if the lipid soluble non-polar compound is not metabolized to the
polar water soluble compound, it will remain in the blood and tissues and
maintain their pharmacologic effects for an indefinite time.
 PHASES OF DRUG METABOLISM:
PHASE 1 METABOLISM PHASE 2 METABOLISM

DEGRADATIVE REACTION (HYDROLYSIS, SYNTHETIC REACTION

OXIDATION, REDUCTION)

INTRODUCTION OF FUNCTIONAL GROUP CONJUGATES PHASE 1 METABOLITE WITH

(-OH, -NH2, -SH, -O, -COOH) GLUCURONIC ACID, SULFATE, ACETYL,
METHYL GROUP)

MAINLY MICROSOMAL MICROSOMAL, MITOCHONDRIAL, &

CYTOPLASMIC

METABOLITES FORMED MAY BE SMALLER, METABOLITES FORMED ARE USUALLY

POLAR/NON-POLAR, ACTIVE/INACTIVE LARGER, POLAR, WATER SOLUBLE &
INACTIVE
ENZYMES INVOLVED IN METABOLISM:

A) ENZYMES INVOLVED IN PHASE 1 REACTIONS:

OXIDATIVE ENZYME:
e.g: Cytochrome P-450 family and the Flavoprotein Monoamino Oxidases –
MAO, and –DAO. Non P-450 Enzymes e.g: Flavin containing
Monooxygenases, Xanthine Dehydrogenase, Aldehyde Oxidase.
There are two types of these enzymes:
1) Microsomal enzyme: cytochrome P-450 family, -MAO, -DAO.

Microsomal
Enzymes

Found in Smooth ER Cytochrome P-450

cells or liver family, -MAO, -DAO
ENZYME INVOLVED IN METABOLISM:
2) Non-Microsomal enzymes: Non P-450 enzymes e.g: Flavin containing
Monooxygenases, Xanthine Dehydrogenases, Aldehyde Oxidase.
Non Microsomal
enzymes

Found in cytoplasm Flavin containing

and mitochondrial cells Monooxygenases,
HYDROLYTIC ENZYME: e.g Esterases, and Amidases. Xanthine
REDUCTIVE ENZYME: e.g Aldo-Keto reductases Dehydrogenase
B) ENZYME INVOLVED IN PHASE 2 REACTIONS:
e.g: Various transferases like glucuronyl transferases, methyl transferases,
acetyl transferases.
These enzymes are found in high concentrations mainly in liver, lungs,
kidneys, GIT, nasal mucosa, skin and brain.
FACTORS AFFECTING
METABOLISM: • Functional Groups in Drug Molecules
• Lipophilicity and Hydrophilicity
• Prodrug Activation
• Stereochemistry (Chirality)
CHEMICAL • Stability and Susceptibility to Biotransformation
FACTORS: • Enzyme Induction and Inhibition

• Age
• Genetic Variability (Pharmacogenetics)
• Sex Differences
• Enzyme Induction/Inhibition by Drugs and Diet
• Liver Function (Hepatic Disease)
BIOLOGICAL • Nutritional Status
FACTORS: • Co-existing Diseases

• Molecular Weight and Size

• Solubility (Hydrophilic vs. Lipophilic Drugs)
• Ionization State (pKa of Drug)
• Protein Binding
PHYSICOCHEMIC • Partition Coefficient (Log P Value)
AL FACTORS: • First-Pass Metabolism
CHEMICAL FACTORS:
Functional Groups in Drug Molecules:
The presence of specific functional groups like hydroxyl (-OH), amine (-NH₂),
carboxyl (-COOH), and sulfhydryl (-SH) influences how the drug is
metabolized.
Phase I metabolism (oxidation, reduction, hydrolysis) often modifies these
groups, making the drug more polar for further processing.
Example: Paracetamol (acetaminophen) undergoes hydroxylation to form
reactive intermediates.
Lipophilicity and Hydrophilicity:
Lipophilic drugs require extensive metabolism to become more water-soluble
for elimination.
Hydrophilic drugs are excreted more easily and may require minimal
metabolism.
Example: Diazepam, a highly lipophilic drug, undergoes multiple metabolic
steps before excretion.
Prodrug Activation:
Some drugs are administered as prodrugs that require metabolic conversion
into their active form.
Example: Enalapril is a prodrug that is converted into enalaprilat in the liver.
CHEMICAL FACTORS:
Stereochemistry (Chirality):
Many drugs exist as enantiomers (mirror-image isomers) that may be
metabolized differently.
Example: Warfarin exists as R- and S-enantiomers; the S-enantiomer is more
potent and metabolized by CYP2C9.
Stability and Susceptibility to Biotransformation:
Some drugs are more susceptible to oxidation, hydrolysis, or conjugation
reactions.
Example: Ester-containing drugs like aspirin undergo hydrolysis to form
salicylic acid.
Enzyme Induction and Inhibition:
Some drugs induce metabolic enzymes, increasing metabolism and reducing
drug efficacy.
Other drugs inhibit metabolic enzymes, leading to drug accumulation and
toxicity.
Example: Rifampin induces CYP450 enzymes, while ketoconazole inhibits
CYP3A4.
BIOLOGICAL FACTORS:
Genetic Variability (Pharmacogenetics):
Genetic differences in drug-metabolizing enzymes affect drug clearance
rates.
Example: Poor metabolizers of CYP2D6 have reduced codeine activation to
morphine, leading to ineffective pain relief.
Age:
Neonates have immature liver enzyme systems, leading to slower
metabolism and prolonged drug effects.
Elderly individuals may have reduced liver function, decreasing metabolic
clearance.
Example: Theophylline metabolism is slow in neonates due to immature
CYP1A2.
Sex Differences:
Males and females metabolize some drugs differently due to hormonal
influences.
Example: Women metabolize benzodiazepines and some cardiovascular
drugs more slowly than men.
BIOLOGICAL FACTORS:
Enzyme Induction/Inhibition by Drugs and Diet:
Certain drugs or foods can increase (induce) or decrease (inhibit) enzyme
activity.
Example: Inducers (increase metabolism): Rifampin, carbamazepine Inhibitors
(reduce metabolism): Grapefruit juice (inhibits CYP3A4), erythromycin
Liver Function (Hepatic Disease):
The liver is the primary site of drug metabolism, so hepatic impairment can
reduce metabolism, increasing drug half-life.
Example: Cirrhosis reduces clearance of drugs like propranolol and diazepam.
Nutritional Status:
Malnutrition can affect enzyme activity due to deficiencies in proteins,
vitamins (B-complex), and essential cofactors.
Example: Alcoholics with poor nutrition have altered metabolism of ethanol
and other drugs.
Co-existing Diseases:
Renal disease: Affects elimination of metabolites.
Cardiac disease: Reduces hepatic blood flow, slowing metabolism.
Liver disease: Decreases enzyme activity, prolonging drug action.
Example: In heart failure, metabolism of lidocaine is significantly reduced.
PHYSICO-CHEMICAL FACTORS:
Molecular Weight and Size:
Smaller molecules are often more readily metabolized, whereas larger
molecules may require multiple steps.
Example: Small drugs like caffeine undergo rapid metabolism.
Solubility (Hydrophilic vs. Lipophilic Drugs):
Lipophilic drugs require metabolism to increase polarity for elimination.
Hydrophilic drugs are eliminated easily without extensive metabolism.
Example: Morphine (hydrophilic) undergoes direct conjugation for
excretion.
Ionization State (pKa of Drug):
Ionized (charged) drugs are more water-soluble, while non-ionized drugs
are more lipid-soluble.
Example: Weak acids like aspirin are absorbed in the stomach and
metabolized in the liver.
PHYSICO-CHEMICAL FACTORS:
Protein Binding:
Drugs highly bound to plasma proteins (e.g., albumin) have slower
metabolism since only free (unbound) drug is metabolized.
Example: Warfarin is highly protein-bound, leading to a longer half-life.
Partition Coefficient (Log P Value):
Determines a drug’s ability to cross membranes and access metabolic
enzymes.
Example: Highly lipophilic drugs (e.g., diazepam) undergo extensive
hepatic metabolism.
First-Pass Metabolism:
Drugs administered orally undergo first-pass metabolism in the liver,
reducing bioavailability.
Example: Propranolol and morphine have significant first-pass effects.
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