Phase I metabolism (oxidation, reduction, hydrolysis)

Phase I Intro - Making Drugs Polar

• Goal: ↑ drug polarity & water solubility to facilitate excretion.
• Mechanism: Introduces or unmasks polar functional groups (e.g., -OH, -NH₂, -SH).
• Key Reactions: 📌 ROH
  • Reduction
  • Oxidation (most common, uses CYP450)
  • Hydrolysis
• The resulting metabolite can be active, inactive, or toxic. It's now prepped for Phase II conjugation or direct renal elimination.

⭐ Most Phase I reactions are catalyzed by the Cytochrome P450 (CYP450) enzyme system located in the smooth endoplasmic reticulum of hepatocytes.

Cytochrome P450 - The Liver's MVP

• Heme-containing monooxygenase superfamily in the hepatic smooth endoplasmic reticulum.
• Catalyzes the oxidation of many drugs, facilitating their excretion.
• General Reaction: $Drug + O_2 + NADPH + H^+ \rightarrow Drug-OH + H_2O + NADP^+$

• Inducers (↑ metabolism): Rifampin, Carbamazepine, Phenobarbital, Phenytoin, St. John's Wort.
• Inhibitors (↓ metabolism): Grapefruit juice, Cimetidine, Macrolides, Azole antifungals, Protease inhibitors.
  • 📌 Mnemonic (Inhibitors): CRACK AMIGOS

⭐ Exam Favorite: CYP3A4 is the most abundant isoform, metabolizing over 50% of clinically used drugs. Its inhibition (e.g., by grapefruit juice) can lead to toxic drug levels.

The Reactions - Oxidation, Reduction, Hydrolysis

• Oxidation: The most common reaction, primarily via Cytochrome P450 (CYP450) enzymes.
  • Adds or unmasks polar functional groups (e.g., -OH, -NH2).
  • Reactions include hydroxylation, dealkylation, and deamination.
• Reduction: Less frequent; involves adding hydrogen or removing oxygen.
  • Catalyzed by reductases (e.g., carbonyl reductase).
  • Example: Naloxone metabolism.
• Hydrolysis: Cleavage by adding water, crucial for esters and amides.
  • Occurs in the liver, plasma, and GI tract.
  • Mediated by esterases (e.g., for aspirin) and amidases (e.g., for procainamide).

⭐ Phase I reactions don't always inactivate a drug; they can convert a prodrug into its active form (e.g., codeine to morphine).

Clinical Impact - Inducers & Inhibitors

High‑Yield Points - ⚡ Biggest Takeaways

• Phase I reactions aim to increase polarity of drugs by unmasking or adding functional groups (-OH, -NH₂).
• The cytochrome P450 (CYP450) system, located in the hepatic smooth ER, is the primary catalyst for these reactions.
• Oxidation is the most common Phase I reaction; reduction and hydrolysis are others.
• These reactions can activate prodrugs or prepare compounds for Phase II conjugation.
• CYP inhibitors (e.g., grapefruit juice, macrolides) can ↑ drug toxicity.
• CYP inducers (e.g., rifampin, St. John's wort) can cause ↓ therapeutic failure.