Biotransformation and Metabolism Pathways

Intro to Biotransformation - Body's Cleanup Crew

• Definition: Chemical alteration of xenobiotics (drugs, toxins) & endogenous compounds within the body.
• Primary Goal: Convert lipophilic (fat-soluble) compounds into more hydrophilic (water-soluble) metabolites for easier excretion, primarily via urine or bile.
• Primary Site: Liver (smooth endoplasmic reticulum, cytosol).
  • Other sites: GIT, lungs, kidneys, skin, plasma.
• Consequences:
  • Inactivation of active drug (most common).
  • Conversion of active drug to active metabolite.
  • Conversion of inactive drug (prodrug) to active drug.
  • Conversion to toxic metabolite.

⭐ Most drugs are lipid-soluble, weak acids or bases, non-polar, and therefore readily reabsorbed by renal tubules. Biotransformation makes them polar & water-soluble for excretion.

Phase I Reactions - Getting Functional

• Goal: Introduce/unmask polar functional groups (-OH, -NH2, -SH) → ↑ polarity & water solubility for excretion.
• Reaction Types: Oxidation (most common), Reduction, Hydrolysis. (📌 Mnemonic: HOR).
• Cytochrome P450 (CYP450) System:
  • Primary enzymes in liver Smooth Endoplasmic Reticulum (microsomes).
  • Requires: CYP450 (hemoprotein), NADPH-CYP450 reductase, NADPH, O2.
  • Reaction: $Drug + O_2 + NADPH + H^+ \rightarrow Drug-Metabolite + H_2O + NADP^+$
  • Key isoforms: CYP3A4/5 (metabolizes ~50% drugs), CYP2D6, CYP2C9, CYP2C19, CYP1A2.
• Non-CYP450 Enzymes:
  • Alcohol/aldehyde dehydrogenase, xanthine oxidase, Monoamine Oxidase (MAO), esterases, amidases.
• Outcome: Metabolites: active, inactive, or toxic. Prodrugs often activated.

⭐ Grapefruit juice potently inhibits intestinal CYP3A4, leading to ↑ bioavailability & risk of toxicity of drugs like statins and calcium channel blockers (CCBs).

Phase II Reactions - Conjugation Junction

• Drug/metabolite + endogenous molecule → polar, excretable conjugate.
• Goal: ↑ water solubility, ↑ molecular weight, ↓ pharmacological activity.
• Reactions primarily cytosolic (except glucuronidation: ER).
• Require activated cofactors (e.g., UDP-glucuronic acid).
• Major Pathways:
  • Glucuronidation: Most common. Enzyme: UDP-glucuronosyltransferase (UGT). Substrates: Bilirubin, morphine, paracetamol.

    ⭐ Neonates have deficient UGT activity, risking Gray Baby Syndrome with chloramphenicol.

  • Sulfation: Enzyme: Sulfotransferase (SULT). Substrates: Steroids, paracetamol.
  • Acetylation: Enzyme: N-acetyltransferase (NAT). Substrates: Isoniazid, sulfonamides. (📌 Slow/Fast acetylators).
  • Glutathione Conjugation: Enzyme: Glutathione S-transferase (GST). Detoxifies NAPQI (paracetamol metabolite).
  • Methylation: Enzyme: Methyltransferase (e.g., TPMT). Substrates: Azathioprine, 6-MP.
  • Amino Acid Conjugation: With glycine, taurine. Substrates: Salicylates. ​

Metabolism Modulators & Clinical Impact - Influencers & Effects

• Enzyme Induction: Process where drug ↑ enzyme synthesis/activity → ↑ its own or other drugs' metabolism.
  • Inducers: Rifampicin, Phenytoin, Barbiturates, Carbamazepine, Griseofulvin, Smoking, Chronic alcohol. (📌 CRAP GPS)
  • Clinical Impact: ↓ active drug efficacy, ↑ active metabolite toxicity, drug tolerance.
• Enzyme Inhibition: Process where drug ↓ enzyme activity → ↓ its own or other drugs' metabolism.
  • Inhibitors: Cimetidine, Omeprazole, Ketoconazole, Macrolides (Erythromycin), Grapefruit juice, Valproate, Isoniazid, Allopurinol. (📌 G-VICK MA)
  • Clinical Impact: ↑ active drug toxicity, ↓ prodrug activation & efficacy.

• Genetic Factors (Pharmacogenomics):
  • CYP450 gene polymorphisms (e.g., CYP2D6, CYP2C19, CYP2C9) → variable enzyme activity.
  • E.g., Slow acetylators of Isoniazid → ↑ risk of neuropathy/hepatotoxicity.
  • Rapid metabolizers → may require ↑ doses for therapeutic effect.
• Other Influencers:
  • Age: Neonates & elderly → ↓ metabolic capacity.
  • Disease: Liver disease (e.g., cirrhosis) → significantly ↓ metabolism.
  • Diet & Environment: Charcoal broiled food (inducer), grapefruit juice (inhibitor).

⭐ Grapefruit juice inhibits intestinal CYP3A4, significantly ↑ bioavailability and risk of toxicity of drugs like statins (Simvastatin, Atorvastatin), Nifedipine, and Cyclosporine. This interaction is clinically significant and often tested.

High‑Yield Points - ⚡ Biggest Takeaways

• Phase I reactions (oxidation, reduction, hydrolysis) primarily involve CYP450 enzymes, making drugs more polar.
• Phase II reactions (conjugation, e.g., glucuronidation) further ↑ water solubility for renal excretion.
• CYP450 inducers (e.g., Rifampicin, Phenobarbital) ↓ drug effect; inhibitors (e.g., Ketoconazole, Grapefruit juice) ↑ drug effect/toxicity.
• First-pass metabolism, mainly in the liver, significantly ↓ bioavailability of many oral drugs.
• Genetic polymorphisms (e.g., CYP2D6, NAT2) cause variable drug metabolism and patient responses.