Drug Metabolism

Drug Metabolism Basics & Phase I - Kickstarting Cleanup

Drug metabolism (biotransformation) converts lipophilic drugs into more polar, hydrophilic metabolites for easier excretion.

• Primary Site: Liver (microsomes in SER). Others: GIT, lungs, kidney.
• Phases:
  • Phase I: Functionalization (introduce/unmask polar group).
  • Phase II: Conjugation (add endogenous substrate).

Phase I Reactions: "Kickstart" drug inactivation & excretion.

• Types: Oxidation, Reduction, Hydrolysis (📌 Mnemonic: OHR).
• Cytochrome P450 (CYP450) System:
  • Major enzyme family for Phase I. Located in hepatic SER.
  • Requires: NADPH, $O_2$.
  • Mechanism: Drug + $O_2$ + $NADPH + H^+$ $\rightarrow$ Drug-OH + $H_2O$ + $NADP^+$.
  • Key Isoforms: CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2.
    • CYP3A4 metabolizes ~50% of drugs.
• Other Enzymes: Alcohol/aldehyde dehydrogenases, esterases, amidases, Flavin-containing monooxygenases (FMOs).

⭐ CYP3A4, the most abundant hepatic isoform, metabolizes ~50% of clinical drugs, highlighting its critical role.

Phase II Reactions - Tag & Toss Conjugation

Purpose: Significantly increases water solubility of xenobiotics, reduces pharmacological activity, and facilitates their renal or biliary excretion. Mechanism: Involves covalent attachment (conjugation) of an endogenous polar molecule to a functional group on the drug or its Phase I metabolite.

Factors & Clinical Relevance - Modulators & Mayhem

• Genetic Factors:
  • Pharmacogenomics: Gene variations (e.g., CYP2D6, NAT2) alter drug response.
  • Slow/fast acetylators (NAT2); poor/ultrarapid metabolizers (CYP2D6).
• Physiological Factors:
  • Age: Neonates & elderly ↓ metabolism.
  • Disease: Liver/kidney disease ↓ metabolism.
  • Pregnancy: Variable effects.
• Environmental Factors:
  • Diet: Grapefruit juice ↓ CYP3A4.
  • Smoking: ↑ CYP1A2 (e.g., theophylline).
  • Alcohol: Acute ↓, chronic ↑ metabolism.
• Drug Interactions (DDIs):
  • Enzyme Induction: ↑ metabolism, ↓ drug efficacy or ↑ toxic metabolite.
    • Inducers: Rifampicin, Phenytoin, Carbamazepine, Barbiturates, St. John's Wort. 📌 CRAP GPS.
  • Enzyme Inhibition: ↓ metabolism, ↑ drug efficacy or ↑ toxicity.
    • Inhibitors: Cimetidine, Ketoconazole, Erythromycin, Grapefruit juice. 📌 SICKFACES.COM.
• Clinical Significance:
  • Adverse Drug Reactions (ADRs), DDIs, therapeutic failure.
  • Dose individualization, Therapeutic Drug Monitoring (TDM).

⭐ Warfarin dose adjustments based on CYP2C9 & VKORC1 genotypes are crucial to prevent bleeding/clotting.

High‑Yield Points - ⚡ Biggest Takeaways

• Phase I reactions (oxidation, reduction, hydrolysis) increase drug polarity, mainly via Cytochrome P450 (CYP450).
• CYP450 inducers (e.g., rifampicin, phenobarbital) ↓ drug effect; inhibitors (e.g., ketoconazole, erythromycin) ↑ toxicity.
• Phase II reactions (conjugation: glucuronidation, sulfation) make drugs water-soluble for excretion.
• Glucuronidation is key in Phase II; deficient in Gilbert's & Crigler-Najjar syndromes.
• Slow acetylators (genetic variation) risk ↑ toxicity from drugs like isoniazid.
• Grapefruit juice inhibits CYP3A4, significantly ↑ drug bioavailability_._