Pharmacokinetics: Metabolism and Excretion

Biotransformation: Overview - Chemical Makeovers

• Definition: Enzymatic chemical alteration of drugs, primarily in the liver.
• Purpose: Convert lipophilic drugs to more polar (water-soluble) metabolites for easier renal excretion.
• Key Sites:
  • Liver (dominant)
  • GIT, Lungs, Kidneys, Skin, Plasma
• Reaction Phases:
  • Phase I (Functionalization): Oxidation, reduction, hydrolysis. Introduces/unmasks a functional group.
  • Phase II (Conjugation): Covalent attachment of an endogenous molecule (e.g., glucuronide).

⭐ The cytochrome P450 (CYP450) enzyme system, predominantly in the liver, is crucial for Phase I metabolism of many drugs.

Phase I Metabolism: CYP Enzymes - CYP Showdown

• Reactions: Oxidation (main), Reduction, Hydrolysis, Cyclization, Decyclization. Goal: ↑polarity for excretion.
• Location: Primarily liver (smooth endoplasmic reticulum), also GI tract, lungs, kidneys.
• Key Enzymes & Significance:
  • CYP3A4/5: Metabolizes ~50% of clinically used drugs.
  • CYP2D6: Marked genetic polymorphism (e.g., codeine efficacy, tamoxifen activation).
  • CYP2C9: Metabolizes warfarin (narrow therapeutic index).
  • CYP2C19: Activates clopidogrel; polymorphism affects efficacy.
• CYP Inducers: ↑Enzyme synthesis → ↑Metabolism → ↓Drug plasma concentration & effect (or ↑active metabolite).
  • 📌 CRAP GPS induces my rage!: Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbital, Smoking/St. John's Wort.
• CYP Inhibitors: ↓Enzyme activity → ↓Metabolism → ↑Drug plasma concentration & risk of toxicity.
  • 📌 SICKFACES.COM Group: Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Chloramphenicol, Erythromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole, Grapefruit juice.

⭐ Grapefruit juice is a potent inhibitor of intestinal CYP3A4, significantly increasing the bioavailability and risk of toxicity of many drugs like statins and calcium channel blockers.

Phase II Metabolism: Conjugation - Conjugation Crew

• Synthetic reactions: drug + endogenous substrate → conjugate.
• Purpose: ↑ water solubility, ↑ excretion.
• Key Reactions:
  • Glucuronidation: UGT; UDP-glucuronic acid. Most common.
  • Acetylation: NAT; Acetyl-CoA. (📌 Polymorphism: Slow/Fast acetylators - Isoniazid, Hydralazine, Procainamide - "SHIP")
  • Sulfation: SULT; PAPS.
  • Methylation: Methyltransferase; SAM.
  • Glutathione Conjugation: GST; GSH. Detoxifies electrophiles.
• Usually inactivates drugs (e.g., Morphine-6-glucuronide is active).

⭐ N-acetyltransferase (NAT2) polymorphism causes slow/fast acetylator status, affecting toxicity (e.g., isoniazid neuropathy in slow acetylators).

Drug Excretion: Renal & Others - The Great Escape

• Main Route: Kidneys. Others: Biliary, pulmonary, saliva, sweat, milk.
• Renal Mechanisms:
  • Glomerular Filtration (GF): Unbound drug; depends on GFR.
  • Tubular Reabsorption: Passive (lipid-soluble, non-ionized). Ion trapping (↑ ionized drug, e.g., $A^-$, $BH^+$): acidic drugs → alkaline urine; basic drugs → acidic urine. 📌 Urine pH change traps ionized drug.
  • Tubular Secretion: Active (OATs, OCTs), saturable, competition.
• Factors Affecting Renal Excretion:

• Biliary Excretion: Drugs >300 Da MW, conjugates. Enterohepatic circulation.
• Milk: Basic, lipid-soluble drugs. ⚠️ Risk to nursing infant.

⭐ Alkalinization of urine (e.g., NaHCO₃) enhances excretion of acidic drugs (Aspirin); acidification (NH₄Cl) for basic drugs (Amphetamine).

Clinical Pharmacokinetics: Metabolism & Excretion - Dose & Duration

• Clearance ($Cl$): Rate of drug elimination. $Cl = (0.693 \times Vd) / t½$. Governs maintenance dose.
• Half-life ($t½$): Time for drug concentration to decrease by 50%. $t½ = (0.693 \times Vd) / Cl$. Determines dosing interval; steady state reached in 4-5 $t½$.
• First-pass metabolism: Hepatic/gut wall metabolism before systemic circulation; ↓ bioavailability (e.g., lignocaine, propranolol).
• Factors: Genetic (e.g., slow/fast acetylators 📌 INH), liver/kidney disease (↓ $Cl$, ↑ $t½$).

⭐ Steady state concentration ($Css$) is achieved after approximately 4-5 elimination half-lives of a drug when administered by continuous infusion or fixed intermittent doses.

High‑Yield Points - ⚡ Biggest Takeaways

• Phase I reactions (oxidation, reduction, hydrolysis) via CYP450 make drugs polar.
• Phase II reactions (conjugation, e.g., glucuronidation) form highly polar, inactive, excretable metabolites.
• Enzyme induction (e.g., rifampicin, phenytoin) ↑ metabolism, ↓ drug effect.
• Enzyme inhibition (e.g., ketoconazole, erythromycin) ↓ metabolism, ↑ drug toxicity.
• First-pass metabolism in liver significantly ↓ oral drug bioavailability.
• Zero-order kinetics: constant amount eliminated/time (e.g., Warfarin, Aspirin, Tolbutamide, Ethanol, Phenytoin).