PHARMACOKINETICS, ABSOLUTE BIOAVAILABILITY, AND DISPOSITION OF [C-14]NEFAZODONE IN HUMANS

The pharmacokinetics and disposition of nefazodone (NEF) were investig ated after administration of intravenous (iv) and oral (po) doses to n ine healthy men, All volunteers were administered a 5-mg dose of [C-14 ]NEF by iv infusion on study day 1, and groups of three volunteers eac h were administered oral solution doses of 50, 100, and 200 mg of [C-1 4]NEF, respectively, on study day 8. Total radioactivity in plasma, ur ine, and feces collected for 7 days after iv and po dosing was determi ned, Serial blood samples for pharmacokinetic analysis were also colle cted over a 48-hr period after iv and po administrations, and plasma s amples were assayed for NEF, and the NEF metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) by a specific, validated HPLCmethod, Over the po dose range of 50-200 mg, NEF was rapidly abso rbed (t(max) values for NEF, HO-NEF and total radioactivity were appro ximate to 0.5 hr). Recovery of total radioactivity in the urine (appro ximate to 50% of dose) was similar after iv and po administrations. Fe cal excretion of radioactivity after iv administration of [C-14]NEF su ggested 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, Th e apparent extent of presystemic metabolism over this dosage range was estimated to be 74-87%, In summary, after pc administration, NEF was rapidly and completely absorbed, and extensively metabolized before el imination via urinary and fecal routes.