first-pass effect

**Definition:** After oral absorption, drugs enter the portal vein and pass through the gut wall and liver before reaching the systemic circulation. Metabolism at these sites (CYP3A4 in enterocytes and hepatocytes, plus P-glycoprotein efflux in the gut) lowers the fraction of active drug that reaches the systemic circulation.

**Key equations:** - Oral bioavailability: F = fraction absorbed × (1 − hepatic extraction ratio) × (1 − gut-wall extraction). - IV administration has F = 1 (100%) by definition. - Hepatic extraction ratio (ER) = (C_in − C_out)/C_in. High-ER drugs (ER >0.7) have a marked first-pass effect. - For high-ER drugs, hepatic clearance is limited by hepatic blood flow (flow-dependent), not by enzyme activity. Changes in liver blood flow (heart failure, cirrhosis with shunting) therefore affect them greatly.

**Classic high first-pass drugs (high-yield):** - Nitroglycerin (~90%+ extracted): given sublingually or transdermally. - Lidocaine: given IV or topically. Oral use is ineffective. - Propranolol and metoprolol: oral doses are much higher than IV doses. - Morphine: oral doses are higher than parenteral doses. - Verapamil - Sumatriptan - Testosterone: oral forms are inactivated, so it is given by injection, patch, or gel, or as methyltestosterone/17-alkylated derivatives. - Insulin and other peptides: degraded in the GI tract, so they are given parenterally. - Others: tacrolimus, cyclosporine (gut CYP3A4), midazolam, buspirone, losartan (prodrug activation).

**Strategies to bypass first pass:** - Sublingual or buccal: drains into the systemic veins (SVC), not the portal vein. - IV, IM, SC, transdermal, inhaled. - Rectal: partial bypass only. The lower and middle rectal veins drain to the IVC, but the superior rectal vein drains to the portal system. - Increase the oral dose (but watch for variability and toxic metabolites).

**Clinical significance:** - *Liver disease (cirrhosis):* decreased first-pass metabolism and portosystemic shunting raise oral bioavailability. Doses of drugs such as propranolol and morphine should be reduced. - *CYP inhibitors* (grapefruit juice inhibits gut CYP3A4, ketoconazole, ritonavir) raise the bioavailability of drugs like simvastatin, felodipine, and cyclosporine. This increases toxicity risk, including rhabdomyolysis with statins. - *CYP inducers* (rifampin, phenytoin, carbamazepine, St. John's wort) lower bioavailability. - *Prodrugs* that require hepatic activation (e.g., enalapril to enalaprilat, codeine to morphine via CYP2D6, clopidogrel) depend on first-pass conversion. - *Neonates:* immature hepatic enzymes reduce first-pass metabolism. - Some drugs (e.g., sumatriptan, dosing of propranolol) show large interpatient variability because of differences in first-pass metabolism.

**Board pearls:** - The first-pass effect decreases bioavailability, not the half-life or volume of distribution directly. - If a question compares oral and IV dose requirements for the same drug, think first-pass effect. - Nitroglycerin: sublingual route, onset in minutes, avoids hepatic first pass. - Lidocaine for arrhythmias must be given IV.