phase I metabolism

**Definition:** Phase I reactions modify a drug into a more polar metabolite. They either add or expose a functional group, preparing the drug for phase II conjugation or direct excretion.

**Reaction types:** - **Oxidation** (most common): hydroxylation, N-/O-dealkylation, deamination, epoxidation, sulfoxidation. Enzymes include CYP450, flavin-containing monooxygenases (FMO), alcohol and aldehyde dehydrogenase, and monoamine oxidase. - **Reduction:** azo and nitro reduction (e.g., by CYP450 reductase or gut flora). - **Hydrolysis:** esterases and amidases (e.g., procaine, succinylcholine by pseudocholinesterase, aspirin, and enalapril to enalaprilat).

**Cytochrome P450 system:** - Heme-containing enzymes in the smooth ER of hepatocytes. Enterocytes also have them, especially CYP3A4. - They use NADPH and O2 to insert one oxygen atom into the substrate. - CYP3A4/5 metabolizes about 50% of drugs. CYP2D6, 2C9, 2C19, and 1A2 are also important.

**Clinical pearls:** - **Inducers** increase CYP activity, which lowers the levels of co-administered drugs (so efficacy falls). Mnemonic: "Guiseppe 'Phen-Phen' Carbamazepine Rides Chronic Sulfa Sundays": Griseofulvin, Phenytoin, Phenobarbital, Carbamazepine, Rifampin, Chronic alcohol use, St. John's wort. - **Inhibitors** decrease CYP activity, which raises the levels of co-administered drugs (toxicity risk). Mnemonic "Sodium Valproate Is Considered Kind of A Cell Giant Quinidine Ritonavir Inhibitor": Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Amiodarone, Grapefruit juice, Quinidine, Ritonavir, Macrolides (except azithromycin), and others. - **Prodrugs** that need phase I activation: codeine to morphine (CYP2D6), clopidogrel (CYP2C19), cyclophosphamide, losartan, azathioprine to 6-MP (this is non-CYP), and enalapril (esterase). - **Toxic metabolites:** acetaminophen is converted by CYP2E1 to NAPQI, which is detoxified by glutathione (a phase II reaction) and depleted in overdose. The antidote is N-acetylcysteine. Ethanol is oxidized by alcohol dehydrogenase and then aldehyde dehydrogenase (blocked by disulfiram). - **Pharmacogenomics:** CYP2D6 ultra-rapid metabolizers given codeine may have morphine toxicity. CYP2C19 poor metabolizers have reduced clopidogrel activation. CYP2C9 variants affect warfarin dosing. Slow vs. fast acetylation (NAT2, which is phase II) is a separate concept. - **Age and disease:** phase I is reduced in neonates, the elderly, and liver disease. It is more vulnerable than phase II. Therefore, in the elderly, drugs that undergo only phase II metabolism (the "LOT" drugs: Lorazepam, Oxazepam, Temazepam) are preferred because they are better preserved. - **Zero-order kinetics** can occur when enzymes saturate (e.g., ethanol, phenytoin, aspirin at high doses).

**Phase I vs Phase II:** - Phase I: functionalization, with products that are slightly more polar and may be active or inactive. It is CYP-dependent and is easily saturated, induced, or inhibited. - Phase II: conjugation (glucuronidation, sulfation, acetylation, glutathione conjugation, methylation, amino acid conjugation) with a large polar group. Products are very polar and usually inactive, and are excreted in urine or bile. Mnemonic: Phase I = "reduction, oxidation, hydrolysis"; Phase II = "conjugation." - Note that the order is not strict: some drugs go directly to phase II (e.g., isoniazid acetylation), and phase II can precede phase I.