Pharmacokinetics | Drug Metabolism

Drug Metabolism Overview
📌 Drug metabolism is essential for excreting drugs, typically by converting the active form into an inactive metabolite to facilitate excretion via urine or feces (biliary system).
🔄 Metabolism can also convert a toxic substance into a non-toxic metabolite or activate a pro-drug (e.g., valacyclovir to acyclovir) via the CYP450 system.
🧪 The three main roles of liver metabolism are: converting toxic to non-toxic, activating pro-drugs, or inactivating active drugs for excretion.

Phase I Biotransformation (CYP450 System)
🛑 Phase I reactions primarily occur in the liver hepatocytes, specifically in the smooth endoplasmic reticulum or mitochondria, involving heme-containing enzymes known as the CYP450 system.
🔥 The most significant enzymes are CYP3A4 (metabolizing about 70-75% of drugs) and CYP2D6, which categorize enzymes by family, subfamily, and isozyme (e.g., CYP2D6).
🛠️ Phase I reactions—oxidation, reduction, or hydrolysis—make non-polar, lipid-soluble drugs more polar and water-soluble for easier excretion.

Factors Affecting Phase I Metabolism
🧬 Genetic Polymorphism: Variations in CYP2D6 function can create rapid metabolizers (increased inactive drug, decreased therapeutic effect) or slow metabolizers (increased active drug, risk of toxicity, demonstrated by codeine metabolism issues).
💊 Drug Interactions (Inducers/Inhibitors): Inducers increase CYP450 activity, speeding up metabolism (e.g., increasing inactive warfarin, risking clotting); Inhibitors decrease activity, mimicking slow metabolizers (e.g., decreasing active warfarin, risking bleeding).
📉 Organ Function and Age: Liver disease (cirrhosis, failure) decreases CYP450 efficacy, leading to toxicity; metabolism is also decreased in infants and the elderly.

Phase II Biotransformation (Conjugation Reactions)
💧 Phase II aims to make the drug even more polar and water-soluble than after Phase I, facilitating urinary or biliary excretion.
✨ Phase II utilizes transferase enzymes to perform conjugation reactions, adding chemical groups such as methyl, acetyl, sulfur, glutathione, or glucuronate molecules onto the drug.
🔗 Conjugation reactions (e.g., glucuronidation) are distinct from Phase I reactions and do not rely on the CYP450 system; not all drugs must pass through both Phase I and Phase II sequentially.

Key Points & Insights
➡️ Drug metabolism prioritizes converting active drugs to inactive, water-soluble metabolites to ensure efficient excretion from the body.
➡️ Inhibitors of CYP450 enzymes act like slow metabolizers, increasing the concentration of the active drug, which can lead to toxicity (e.g., high warfarin levels causing bleeding).
➡️ Inducers of CYP450 enzymes accelerate metabolism, potentially leading to sub-therapeutic effects due to rapid conversion of the active drug to its inactive form (e.g., reduced anti-platelet activity from clopidogrel).
➡️ A critical clinical example involves omeprazole (a potent CYP450 inhibitor) reducing the activation of the pro-drug clopidogrel, leading to reduced anti-platelet activity and high risk for MI.

📸 Video summarized with SummaryTube.com on Mar 09, 2026, 17:14 UTC