Pharmacokinetics, absolute bioavailability, and disposition of [14C]nefazodone in humans

The pharmacokinetics and disposition of nefazodone (NEF) were investigated after administration of intravenous (iv) and oral (po) doses to nine healthy men. All volunteers were administered a 5-mg dose of [14C]NEF by iv infusion on study day 1, and groups of three volunteers each were administered oral solution doses of 50, 100, and 200 mg of [14C]NEF, respectively, on study day 8. Total radioactivity in plasma, urine, and feces collected for 7 days after iv and po dosing was determined. Serial blood samples for pharmacokinetic analysis were also collected over a 48-hr period after iv and po administrations, and plasma samples were assayed for NEF, and the NEF metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) by a specific, validated HPLC method. Over the po dose range of 50-200 mg, NEF was rapidly absorbed (tmax values for NEF, HO-NEF and total radioactivity were approximately 0.5 hr). Recovery of total radioactivity in the urine (approximately 50% of dose) was similar after iv and po administrations. Fecal excretion of radioactivity after iv administration of [14C]NEF suggested that biliary excretion also plays a role in drug elimination. The mean (SD) apparent absolute oral bioavailability of NEF was 15(7)%, 18(7)%, and 23(7)% at doses of 50, 100, and 200 mg, respectively. The apparent extent of presystemic metabolism over this dosage range was estimated to be 74-87%. In summary, after po administration, NEF was rapidly and completely absorbed, and extensively metabolized before elimination via urinary and fecal routes.