Drug metabolism Study Guide

📖 Core Concepts Drug metabolism – enzymatic conversion of a drug (or other xenobiotic) into more water‑soluble forms for excretion. Xenobiotic – any foreign chemical (drug, pollutant, poison) that the body must modify. LADME – the fourth step (Metabolism) of Load → Absorption → Distribution → Metabolism → Excretion. Phase I (Modification) – introduces or uncovers polar functional groups (‑OH, ‑COOH, ‑NH₂) via oxidation, reduction, or hydrolysis; key enzymes: Cytochrome P‑450, flavin monooxygenases, ADH, ALDH, MAO, peroxidases. Phase II (Conjugation) – couples the polar group to a large, charged molecule (glutathione, sulfate, glucuronic acid, glycine) using transferases; produces high‑MW, highly hydrophilic metabolites. Phase III (Transport) – ATP‑binding cassette (ABC) transporters (e.g., MRP family) pump anionic conjugates out of cells. First‑pass effect – drugs absorbed from the GI tract are heavily metabolized by the liver before reaching systemic circulation. Cytochrome P‑450 induction → faster metabolism → shorter drug effect; inhibition → slower metabolism → prolonged effect. Therapeutic Index (TI) – safety margin: $$TI = \frac{TD{50}}{ED{50}}$$ Genetic polymorphism – enzyme variants create “slow” vs “rapid” metabolizer phenotypes (e.g., NAT2, CYP2D6, CYP3A4). --- 📌 Must Remember Liver (smooth ER) = primary metabolic organ; first‑pass can reduce oral bioavailability > 70 %. Phase I may activate prodrugs (e.g., cyclophosphamide) or toxify compounds. Phase II usually detoxifies and prevents membrane crossing. Phase III exporters are essential for eliminating Phase II conjugates. Inducers (phenytoin, rifampicin) ↓ drug levels of substrates; inhibitors (ketoconazole, erythromycin) ↑ substrate levels. Slow acetylators → higher risk of isoniazid‑induced neuropathy; rapid acetylators → lower efficacy for certain drugs. Synergy = observed effect > predicted additive; antagonism = observed < predicted. Polymorphisms in CYP2D6 affect metabolism of many antidepressants and β‑blockers; dosing may need genotype‑guided adjustment. --- 🔄 Key Processes Drug Entry – lipophilic xenobiotic diffuses across cell membrane. Phase I – enzyme (e.g., CYP450) inserts an oxygen atom → hydroxylated metabolite. Decision Point – is metabolite sufficiently polar? Yes → excrete directly (urine/bile). No → proceed to Phase II. Phase II – transferase attaches glutathione, sulfate, etc.; creates charged conjugate. Phase III – MRP transporter uses ATP to pump conjugate into bile or urine. First‑Pass (oral drugs) – steps 2‑5 occur in hepatic portal system before systemic distribution. --- 🔍 Key Comparisons Phase I vs Phase II Phase I: adds/uncovers polar groups; can activate or toxify. Phase II: couples to large polar moieties; almost always detoxifies. Enzyme Induction vs Inhibition Induction: ↑ enzyme levels → ↑ clearance → ↓ drug exposure. Inhibition: ↓ enzyme activity → ↓ clearance → ↑ drug exposure. Loewe Additivity vs Bliss Independence Loewe: assumes same mechanism → combined effect = higher dose of one drug. Bliss: assumes independent mechanisms → combined effect = product of individual effects. Rapid vs Slow Acetylators (NAT2) Rapid: fast clearance → lower toxicity, possible sub‑therapeutic levels. Slow: accumulation → higher risk of dose‑related adverse effects. --- ⚠️ Common Misunderstandings “Phase I always detoxifies.” – It can produce reactive, toxic metabolites (e.g., acetaminophen → NAPQI). “All metabolism reduces activity.” – Prodrugs rely on metabolic activation to become active. “Induction is always good.” – Inducing a pro‑drug’s activation can raise toxicity (cyclophosphamide). “Only the liver matters.” – Lungs, kidneys, GI epithelium, and skin also metabolize drugs locally. --- 🧠 Mental Models / Intuition Hydrophobic → Hydrophilic Ladder: 1️⃣ Lipophilic drug crosses membrane → 2️⃣ Phase I adds a “handle” (‑OH, ‑COOH) → 3️⃣ Phase II slaps a big, charged “anchor” (glucuronide, sulfate) → 4️⃣ Phase III ships the anchored drug out. “Gatekeeper” Model: The liver is the first checkpoint (first‑pass) that decides how much of an oral dose reaches the bloodstream. --- 🚩 Exceptions & Edge Cases Toxic Phase I metabolites (e.g., acetaminophen → NAPQI, aflatoxin activation). Pro‑drug activation can be essential (e.g., codeine → morphine via CYP2D6). Extra‑hepatic metabolism can cause localized toxicity (lung CYP enzymes activating inhaled toxins). Polymorphic “ultra‑rapid” metabolizers (CYP2D6) may convert codeine to morphine too quickly → overdose risk. --- 📍 When to Use Which Predict drug‑drug interaction: If both drugs are CYP substrates → check for inducer/inhibitor status. If drugs share the same mechanism, apply Loewe additivity; if independent, apply Bliss independence. Dose adjustment: Slow metabolizer phenotype → lower dose or avoid drugs with narrow therapeutic index. Rapid metabolizer → consider higher dose or alternative agent. Choosing metabolic pathway for drug design: Want high oral bioavailability → design to evade first‑pass (e.g., pro‑drug with limited CYP affinity). Want quick clearance → include functional groups readily handled by Phase I oxidation. --- 👀 Patterns to Recognize Lipophilic → high first‑pass: Large, non‑polar molecules often have low oral bioavailability. “‑ol”, “‑amine”, “‑thiol” → likely substrates for Phase I oxidation/dealkylation. Presence of a phenolic or carboxylic group → good candidates for Phase II glucuronidation or sulfation. Drug‑induced enzyme changes: Chronic rifampicin → ↑ CYP3A4 activity → ↓ plasma levels of many statins. --- 🗂️ Exam Traps Distractor: “Phase I always increases excretion.” – Wrong; some Phase I metabolites need Phase II before excretion. Distractor: “Induction reduces drug toxicity.” – Not true for pro‑drugs that require activation. Distractor: “All CYP inhibitors raise the same drug’s level equally.” – Inhibition strength varies (competitive vs mechanism‑based). Distractor: “Slow acetylators are always at risk of toxicity.” – Only for drugs primarily cleared by NAT2; other pathways may compensate. Distractor: “First‑pass effect only matters for oral drugs.” – Intravenous drugs can be metabolized by extra‑hepatic sites (e.g., lung CYPs). ---