Pharmacology: Pharmacokinetics – Metabolism and Excretion
Intended Learning Outcomes
By the end of this lecture, you should be able to:
1. Identify the properties of Phase I and Phase II metabolism reactions and their
enzymes.
2. Describe the Cytochrome P-450 system and its role in drug metabolism.
3. Differentiate between enzyme induction and inhibition, with examples.
4. Recognize factors affecting drug metabolism and excretion.
5. Understand key pharmacokinetic parameters like bioavailability, clearance, and
half-life.
Metabolism (Biotransformation) of Drugs
Definition:
- Biochemical modification of drugs and foreign chemicals (xenobiotics) in the
body.
- Converts nonpolar (lipid-soluble) drugs into polar (water-soluble) metabolites to
aid excretion.
- Primary site: Liver, others: Kidney, lungs, intestines, plasma.
General Properties of Metabolism
1. Role:
- Terminates drug action and facilitates elimination.
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- Converts drugs to inactive, less active, or active metabolites.
2. Types of Biotransformation:
- Phase I Reactions (Nonsynthetic): Modify drugs chemically (oxidation,
reduction, hydrolysis).
- Phase II Reactions (Synthetic): Conjugate drugs with endogenous molecules
(glucuronic acid, sulfate).
3. Enzymes:
- Phase I: Cytochrome P-450, dehydrogenases, hydrolases.
- Phase II: Transferases (e.g., glucuronyl transferase, sulfotransferase).
Consequences of Biotransformation
1. Inactive metabolites (e.g., Phenobarbital → Hydroxyphenobarbital).
2. Active metabolites (e.g., Codeine → Morphine).
3. Prodrugs activated by metabolism (e.g., Levodopa → Dopamine).
4. Toxic metabolites in some cases.
Classification of Biotransformation Reactions
Phase I (Nonsynthetic Reactions)
- Introduces functional groups (-OH, -NH2, -SH).
- Prepares drugs for Phase II.
1. Oxidation:
- Adds oxygen or removes hydrogen.
- Catalyzed by Cytochrome P-450 enzymes in the liver.
- Examples: Hydroxylation, deamination, dealkylation.
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2. Reduction:
- Opposite of oxidation, often less common.
- Catalyzed by P-450 enzymes working in reverse.
3. Hydrolysis:
- Breaks ester or amide bonds using hydrolases.
- High enzyme concentration in liver, kidneys, and plasma.
Phase II (Synthetic Reactions)
- Conjugation of Phase I metabolites with endogenous molecules.
- Results in polar, inactive, and water-soluble metabolites for excretion.
- Common reactions:
- Glucuronidation: Addition of glucuronic acid.
- Acetylation: Addition of acetic acid.
- Sulfation: Addition of sulfate.
Cytochrome P-450 Monooxygenase System
Key Features
1. Enzyme families: CYP1, CYP2, CYP3, etc.
- Example: CYP3A4 metabolizes over 50% of clinical drugs.
2. Localization:
- Liver (primary), intestines, adrenals, and reproductive organs.
3. Genetic polymorphism:
- Variations in P-450 enzymes (e.g., CYP2D6) lead to differences in drug
metabolism among individuals and ethnic groups.
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Induction and Inhibition of Liver Enzymes
1. Enzyme Induction:
- Increases drug metabolism by enhancing enzyme synthesis.
- Examples: Rifampicin, carbamazepine, barbiturates.
- Leads to reduced drug efficacy and potential drug interactions.
2. Enzyme Inhibition:
- Decreases drug metabolism by inhibiting enzymes.
- Examples: Erythromycin, ketoconazole, grapefruit juice.
- Increases drug toxicity risk due to higher plasma drug levels.
Excretion of Drugs
Definition:
- Removal of drugs and metabolites from the body via urine, bile, feces, lungs,
saliva, or milk.
Renal Excretion
- Primary route for most drugs.
- Processes:
1. Glomerular Filtration:
- Filters unbound drugs based on size and charge.
2. Active Tubular Secretion:
- Secretes drugs using transporters for acids (OATs) and bases (OBTs).
3. Tubular Reabsorption:
- Nonionized drugs are reabsorbed; ionized drugs remain in urine.
- pH and Ionization:
- Alkaline urine promotes excretion of weak acids (e.g., salicylates).
- Acidic urine promotes excretion of weak bases (e.g., alkaloids).
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Biliary and Fecal Excretion
- Drugs secreted into bile, passed into intestines, and excreted via feces.
- Enterohepatic Circulation: Reabsorption of drugs back into the bloodstream from
the intestine, prolonging drug action.
Other Routes
- Lungs: Exhalation of volatile drugs (e.g., anesthetics, alcohol).
- Milk: Transfer to neonates via breastfeeding.
- Saliva and Sweat: Minor routes for certain drugs.
Key Pharmacokinetic Parameters
Bioavailability
- Fraction of administered drug reaching systemic circulation unchanged.
- Influenced by:
- First-pass metabolism (e.g., propranolol).
- Chemical instability (e.g., insulin in GI enzymes).
- Drug solubility (hydrophobic drugs poorly absorbed).
Volume of Distribution (Vd)
- Hypothetical volume into which a drug is distributed.
Plasma Half-Life (t½)
- Time required for plasma drug concentration to decrease by 50%.
- Clinical importance: Determines dosing intervals and time to steady-state
concentration.
Clearance
- Volume of plasma cleared of a drug per unit time.
- Determines the rate of drug elimination.
