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

In a two-way crossover study, the pharmacokinetics and disposition of nefazodone (NEF) were investigated after intravenous (iv) infusion and oral (po) gavage of a solution of 10 mg/kg (5 muCi/kg) of [C-14] NEF to four beagle dogs. Plasma was analyzed by HPLC for NEF, and its meta bolites hydroxynefazodone (HO-NEF), m-chlorophenyl-piperazine (mCPP), and p-hydroxynefazodone (p-HO-NEF). Plasma, urine, and feces were also analyzed for total radioactivity. Mean AUC(INF) values for NEF after po administration were about an order of magnitude lower compared with those after iv administration. Mean C(max) and AUC(INF) values for th e metabolites after po administration were about as high or higher com pared with those after iv administration. Mean (SD) total body clearan ce of NEF was 1.56 (0.34) liter/hr-kg-1, and mean (SD) steady-state vo lume of distribution of NEF was 3.24 (1.0) liter/kg. Mean (SD) absolut e bioavailability of NEF after po administration was calculated to be 14.0 (4.2)%. The fraction of oral NEF eliminated presystemically was e stimated to be 86%. Plasma concentration-time profiles for total radio activity after iv and po administration were superimposable. The recov ery of total radioactivity in urine and feces was similar after iv and po administration, indicating complete absorption of the drug after p o administration. NEF, HO-NEF, and p-HO-NEF accounted for approximatel y 37% and 12% of the plasma AUC for total radioactivity following iv a nd po administration, respectively. The total urinary (28%) and fecal (61%) recovery after iv or po administration was approximately 90% of the dose within 7 days. Data from this study indicates that NEF is rap idly and completely absorbed following po administration and is extens ively metabolized by first-pass effects.