Drug Metabolism and Excretion

Drug Metabolism Basics - Chemical Makeovers

• Biotransformation: Chemical alteration of drugs, primarily in liver (microsomal enzymes, e.g., Cytochrome P450).
• Primary Aim: Convert lipophilic drugs into polar, water-soluble metabolites for enhanced renal excretion.
• Consequences:
  • Inactivation (most common)
  • Activation of prodrugs (e.g., Enalapril → Enalaprilat)
  • Active metabolite from active drug (e.g., Diazepam → Oxazepam)
  • Formation of toxic metabolites (e.g., Paracetamol → NAPQI)
• Two Main Phases:
  • Phase I (Functionalization): Oxidation, Reduction, Hydrolysis. Introduces/unmasks a functional group (e.g., -OH, $-NH_{2}$). Key enzymes: CYP450.
    • 📌 Mnemonic: "ROH" for Reactions - Reduction, Oxidation, Hydrolysis.
  • Phase II (Conjugation): Synthetic. Covalent attachment of endogenous molecule (e.g., glucuronic acid, sulfate). Markedly ↑ water solubility.
    • 📌 Mnemonic: "GAS" for Glucuronidation, Acetylation, Sulfation. and Phase II (conjugation reactions) drug metabolism in liver cells)

⭐ The Cytochrome P450 (CYP) enzyme system is responsible for metabolizing the majority of clinically used drugs.

CYP450 System - Enzyme Powerhouse

• Heme enzymes in liver/intestine; vital for Phase I drug metabolism (oxidation, etc.).
• Nomenclature: e.g., CYP3A4.
  • CYP3A4 metabolizes ~50% drugs. Others: CYP2D6, CYP2C9, CYP1A2.
• Induction: ↑ synthesis → ↑ metabolism → ↓ drug effect / ↑ active metabolite.
  • 📌 Inducers: "CRAPS-G": Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Smoking, Griseofulvin, Phenobarbital.
• Inhibition: ↓ activity → ↓ metabolism → ↑ drug effect/toxicity.
  • 📌 Inhibitors: "MAGIC-K": Macrolides, Amiodarone, Grapefruit Juice, Isoniazid, Cimetidine/Cipro, Ketoconazole (Azoles).
• Genetic Polymorphism: Affects drug response (e.g., CYP2D6 poor/ultra-rapid metabolizers).

⭐ CYP3A4 is the most abundant CYP450, metabolizing ~50% of drugs; grapefruit juice is a potent inhibitor. oka

Drug Excretion Routes - The Exit Strategy

• Renal (Kidney): Primary route.
  • Glomerular Filtration (GF): Unbound drug filtered. GFR-dependent.
  • Active Tubular Secretion (ATS): Proximal tubule. Acids (penicillin), bases (morphine). Saturable.
  • Passive Tubular Reabsorption (PTR): Distal tubule. Lipid-soluble, unionized reabsorbed.
• pH Trapping: ↑ Ionization, ↑ excretion.
  • Acidic drugs (aspirin): Alkalinize urine (NaHCO₃) → ↑ excretion.
  • Basic drugs (amphetamine): Acidify urine (NH₄Cl) → ↑ excretion.
• Hepatic (Biliary): High MW (>300 Da), polar drugs into bile.
  • Enterohepatic Circulation: Gut reabsorption prolongs action (digoxin, morphine).
• Pulmonary: Volatile anesthetics, alcohol.
• Minor: Saliva, sweat, breast milk.

⭐ Probenecid inhibits penicillin's tubular secretion, prolonging action & ↑ plasma levels.

PK in Special Groups - Tailored Dosing

• Elderly: ↓ GFR, ↓ hepatic metabolism (Phase I ↓), ↑ body fat (↑ Vd lipophilic drugs), ↓ body water (↓ Vd hydrophilic drugs), ↓ albumin. Often requires ↓ dose/frequency.
• Neonates/Infants: Immature renal & hepatic functions (e.g., glucuronidation ↓). Risk: Gray Baby Syndrome (chloramphenicol). Dose per kg; avoid certain drugs.
• Renal Impairment: ↓ Excretion of renally cleared drugs & active metabolites. Adjust maintenance dose based on CrCl/eGFR.
  • Cockcroft-Gault: $CrCl \approx \frac{((140 - age) \times Wt_{kg})}{(72 \times SCr_{mg/dL})} (\times 0.85 \text{ if female})$
• Hepatic Impairment: ↓ Metabolism (especially high extraction ratio drugs), ↓ albumin synthesis (↑ free drug). Child-Pugh score guides dosing. Caution with pro-drugs requiring hepatic activation.
• Pregnancy: ↑ GFR (↑ renal clearance), ↑ Vd, ↑ hepatic metabolism (some drugs), placental transfer. May need ↑ doses for some drugs.
• Obesity: ↑ Vd for lipophilic drugs. Dose using IBW or AdjBW for certain drugs.

⭐ In renal failure, the loading dose of most drugs remains unchanged, but the maintenance dose is typically reduced or the dosing interval prolonged to prevent toxicity due to drug accumulation.

High‑Yield Points - ⚡ Biggest Takeaways

• Phase I reactions (oxidation, hydrolysis) via CYP450 ↑ drug polarity.
• Phase II reactions (conjugation, e.g., glucuronidation) ↑ water solubility for excretion.
• CYP450 inducers (e.g., Rifampicin) ↓ drug effect; inhibitors (e.g., Ketoconazole) ↑ toxicity.
• First-pass metabolism (liver/gut) significantly ↓ oral drug bioavailability.
• Renal excretion is key; urine pH alteration (e.g., alkalinize for aspirin) aids elimination.
• Zero-order kinetics (e.g., Phenytoin, Ethanol): constant drug amount eliminated/time.
• Prodrugs (e.g., Enalapril, Levodopa) need metabolic activation for therapeutic effect.