Pharmacokinetics: Metabolism (Biotransformation)
- Subtitle: First-pass metabolism, sites, consequences, types, enzyme inhibition, enzyme induction, and influencing factors.
Introduction to Metabolism
(Biotransformation)
Definition:
Metabolism (Biotransformation) refers to the chemical modification of drugs by
the body, primarily to facilitate their elimination.
Goal:
- Convert lipophilic drugs
into more water-soluble compounds for excretion.
Key
Points:
- Carried out primarily by
enzymes.
- Occurs mostly in the liver
but also in other organs.
Example:
- Codeine is metabolized to
morphine in the liver (bioactivation).
First-Pass Metabolism
Definition:
First-pass metabolism (or pre-systemic metabolism) occurs when drugs are
metabolized in the liver or gut wall before reaching systemic circulation.
Attributes:
- Reduces the bioavailability
of the drug.
- Influences oral drug dosage.
Sites:
- Liver (main site)
- Intestinal wall
- Stomach
Examples:
- Nitroglycerin: Extensive first-pass
effect, hence given sublingually.
- Propranolol: Significant first-pass metabolism in the liver.
Sites of Drug Metabolism
- Liver (Primary Site):
- Contains high levels of
metabolizing enzymes (e.g., cytochrome P450- a group of enzymes).
- Other Sites:
- Kidney
- Gastrointestinal Tract
- Lungs
- Skin
Example:
- Lung: Metabolism of inhaled anesthetics like sevoflurane.
Consequences of Drug Metabolism
- Drug Inactivation:
- Example: Lidocaine is
rapidly inactivated by liver metabolism.
- Drug Activation (Prodrugs → Active
Metabolites):
- Example: Enalapril →
Enalaprilat.
- Toxic Metabolites:
- Example: Acetaminophen
(Paracetamol) → NAPQI (toxic in overdose).
- Altered Drug Action:
- Metabolite may act
differently than the parent drug.
Types of Drug Metabolism
Phase I
Reactions (Functionalization)
- Introduce or unmask
functional groups (-OH, -NH2, -SH).
- Primarily involve oxidation,
reduction, and hydrolysis.
- Enzyme: Cytochrome P450
(CYP) enzymes.
Examples:
- Oxidation: Diazepam →
Nordiazepam
- Hydrolysis: Procaine → PABA
(Para-aminobenzoic acid)
Phase II
Reactions (Conjugation)
- Combine drug/metabolite with
endogenous substrates (e.g., glucuronic acid, sulfate).
- Result: More water-soluble,
excretable compounds.
Examples:
- Glucuronidation: Morphine →
Morphine-6-glucuronide
- Sulfation: Paracetamol → Paracetamol sulfate
Enzyme Inhibition
Definition: Decreased enzyme activity,
slowing drug metabolism.
Consequences:
- Increased drug levels →
Toxicity.
- Drug-drug interactions.
Examples:
- CYP3A4 Inhibition by grapefruit juice →
Increased levels of drugs like simvastatin.
- Ketoconazole: Inhibits CYP enzymes,
increasing warfarin toxicity risk.
Historical
Note:
Grapefruit juice interaction was discovered by accident in 1989 during a
clinical trial.
Enzyme Induction
Definition: Increased synthesis of
metabolic enzymes, enhancing drug metabolism.
Significance:
- Reduces drug efficacy by
increasing its clearance.
Examples:
- Rifampicin: Induces CYP3A4, reducing
oral contraceptive efficacy.
- Carbamazepine: Self-induces its own metabolism over time.
Factors Affecting Drug Metabolism
- Genetic Factors:
- Example: Fast vs. slow
acetylators of isoniazid.
- Age:
- Neonates and elderly have
reduced enzyme activity.
- Sex:
- Differences in hormone
levels can affect metabolism.
- Diet and Environmental
Factors:
- Example: Charcoal-grilled
foods induce CYP1A2.
- Drug-Drug Interactions:
- Example: Warfarin + CYP
enzyme inhibitors (like fluconazole).
- Disease State:
- Liver diseases impair metabolism.
Summary
- Drug metabolism transforms
drugs into active, inactive, or toxic forms.
- First-pass metabolism
affects oral drug bioavailability.
- Metabolism occurs in the
liver (primarily), involving Phase I and Phase II reactions.
- Enzyme inhibition and
induction alter drug levels significantly.
- Various factors, including genetics, diet, and age, influence metabolism.
References
- Textbook of Pharmacology
(Katzung & Trevor).
- Goodman & Gilman's The
Pharmacological Basis of Therapeutics.
END OF THE CHAPTER
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