first-pass metabolism

**Definition & mechanism**: After oral administration, a drug is absorbed in the GI tract and enters the portal vein, passing through the liver before reaching the systemic circulation. Hepatic enzymes (mainly CYP450, especially CYP3A4, plus conjugating enzymes) and intestinal wall enzymes (CYP3A4, P-gp efflux) metabolize a fraction of the drug, so less active drug reaches the systemic circulation.

**Key equations**: - Oral bioavailability: F = (AUC oral / AUC IV) × 100 (IV F = 100%). - F ≈ fraction absorbed × (1 − hepatic extraction ratio) × (1 − gut wall extraction). - Hepatic extraction ratio (ER) = (C in − C out)/C in. High-ER drugs have a large first-pass effect, and their clearance is flow-dependent (limited by hepatic blood flow).

**Classic high first-pass drugs** (low oral bioavailability): nitroglycerin (~<1% oral; use sublingual), lidocaine (not given orally for arrhythmias), propranolol, morphine, verapamil, labetalol, metoprolol, sumatriptan, testosterone (oral), isoproterenol, imipramine/TCAs (e.g., amitriptyline), midazolam, hydrocortisone, and cyclosporine (gut CYP3A4/P-gp).

**Clinical significance**: - **Route selection**: Routes that bypass first pass include IV, IM, SC, sublingual/buccal, transdermal, inhalational, and (partially) rectal. Rectal is only partially protective: the upper rectal veins drain to the portal system, while the middle and inferior rectal veins drain to the systemic circulation via the internal iliac and pudendal veins. - **Dosing**: Oral doses of high-first-pass drugs are much larger than IV doses (e.g., oral morphine is given at a higher dose than IV morphine). - **Liver disease/cirrhosis & portosystemic shunting**: Reduced hepatic metabolism and shunting increase bioavailability, which can lead to toxicity of high-ER drugs (e.g., propranolol, morphine), so dose reduction is needed. - **Drug interactions**: CYP3A4 inhibitors (grapefruit juice, ketoconazole, ritonavir, macrolides) reduce gut and hepatic first-pass metabolism and raise levels of drugs like felodipine, simvastatin, and cyclosporine. CYP inducers (rifampin, phenytoin, carbamazepine, St. John's wort) lower bioavailability. - **Prodrugs**: First-pass activation is required for some drugs (e.g., enalapril → enalaprilat, codeine → morphine via CYP2D6, clopidogrel, losartan). - **Active metabolites**: First pass can produce active metabolites (e.g., propranolol → 4-hydroxypropranolol). - **Nitroglycerin**: Sublingual administration avoids first pass, giving rapid onset for acute angina.

**Board pearls**: - First pass lowers bioavailability, not elimination half-life per se. - Decreased first pass (liver disease, CYP inhibition, shunts) → increased F → possible toxicity. - Heparin, insulin, and other peptides are not given orally primarily because of GI degradation and poor absorption, but they also undergo first-pass metabolism or proteolysis. - Distinguish from **enterohepatic circulation** (biliary excretion and reabsorption) and **presystemic gut metabolism**.