phase II metabolism

**Definition:** Phase II reactions are conjugation (synthetic) reactions in which a polar endogenous substrate is covalently attached to a drug or Phase I metabolite that has a suitable functional group (-OH, -NH2, -SH, -COOH). Products are usually more hydrophilic, larger, and pharmacologically inactive, so they are readily excreted in urine or bile.

**Key reactions and enzymes** - **Glucuronidation (UGT, UDP-glucuronosyltransferase):** Most common Phase II reaction. Uses UDP-glucuronic acid. Located in the endoplasmic reticulum. Examples: morphine (M3G inactive, M6G active), acetaminophen, bilirubin, lorazepam, oxazepam, temazepam, estrogen, and chloramphenicol. - **Sulfation (SULT):** Uses PAPS (3'-phosphoadenosine-5'-phosphosulfate). It is high-affinity but low-capacity and saturable. Examples: acetaminophen, steroids, and methyldopa. - **Glutathione conjugation (GST):** Detoxifies electrophiles, including NAPQI (the toxic acetaminophen metabolite), and also handles ethacrynic acid and busulfan. - **Acetylation (NAT2):** Uses acetyl-CoA. Examples: isoniazid, hydralazine, procainamide, sulfonamides, and dapsone. It shows genetic polymorphism (slow vs rapid acetylators). - **Methylation (TPMT, COMT, HNMT):** Uses SAM. Examples: 6-mercaptopurine and azathioprine (TPMT), catecholamines and levodopa (COMT). - **Glycine/amino acid conjugation:** Salicylates (salicyluric acid) and benzoic acid.

**Phase I vs Phase II** - Phase I (oxidation, reduction, hydrolysis; CYP450) *unmasks or adds* a functional group. Products may be active, inactive, or toxic (for example, prodrug activation). - Phase II *conjugates*. Products are usually inactive, with exceptions (morphine-6-glucuronide is active; minoxidil sulfate is the active form). - Phase I is more affected by age, liver disease, and drug interactions, and it is more subject to induction and inhibition. Phase II is relatively preserved, which is why the benzodiazepines **L**orazepam, **O**xazepam, and **T**emazepam (glucuronidated directly) are preferred in the elderly and in patients with cirrhosis. - Not every drug goes through Phase I first. Some are conjugated directly, and the order is not strict.

**High-yield clinical correlations** - **Acetaminophen:** At therapeutic doses it is mostly glucuronidated and sulfated. A small fraction goes through CYP2E1 to NAPQI, which is detoxified by glutathione conjugation. In overdose, sulfation and glucuronidation saturate and glutathione is depleted, so NAPQI accumulates and causes centrilobular (zone 3) hepatic necrosis. Treatment is N-acetylcysteine (NAC), which replenishes glutathione. - **Neonatal physiology:** Immature UGT1A1 in newborns causes physiologic jaundice (unconjugated hyperbilirubinemia). It also causes **gray baby syndrome** with chloramphenicol, which is not glucuronidated adequately. - **UGT1A1 deficiency:** Crigler-Najjar types I and II (severe or absent activity; type II responds to phenobarbital) and Gilbert syndrome (mild reduction, with benign, stress-induced unconjugated hyperbilirubinemia). Irinotecan's active metabolite SN-38 is cleared by UGT1A1, so patients with UGT1A1*28 are at higher risk of toxicity. - **NAT2 slow acetylators:** At higher risk of isoniazid-induced peripheral neuropathy (prevent with pyridoxine/B6), hydralazine- or procainamide-induced lupus, and sulfonamide toxicity. - **TPMT deficiency:** Azathioprine and 6-MP cause severe myelosuppression, so check TPMT genotype or activity before use. - **Inducers:** Phenobarbital induces UGT. Phase II enzymes are less commonly induced than CYP450. - **Enterohepatic circulation:** Glucuronides excreted in bile can be deconjugated by gut bacterial β-glucuronidase and reabsorbed. Antibiotics may interrupt this process. - **Hepatic first-pass:** Conjugation in the gut wall and liver contributes to low oral bioavailability (for example, morphine).

**Quick memory aid:** Phase I = "functionalization" (CYP450, reactive); Phase II = "conjugation" (transferases, inactivating). Geriatric-safe benzos (LOT) skip CYP oxidation and go straight to glucuronidation.