Pharmacokinetics, absolute bioavailability, and disposition of [14C]nefazodone in the dog.
In a two-way crossover study, the pharmacokinetics and disposition of nefazodone (NEF) were investigated after intravenous (i.v.) infusion and oral (po) gavage of a solution of 10 mg/kg (5 microCi/kg) of [14C]NEF to four beagle dogs. Plasma was analyzed by HPLC for NEF, and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (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 i.v. administration. Mean Cmax and AUC(INF) values for the metabolites after po administration were about as high or higher compared with those after i.v. administration. Mean (SD) total body clearance of NEF was 1.56 (0.34) liter/hr.kg-1, and mean (SD) steady-state volume of distribution of NEF was 3.24 (1.0) liter/kg. Mean (SD) absolute bioavailability of NEF after po administration was calculated to be 14.0 (4.2)%. The fraction of oral NEF eliminated presystemically was estimated to be 86%. Plasma concentration-time profiles for total radioactivity after i.v. and po administration were superimposable. The recovery of total radioactivity in urine and feces was similar after iv and po administration, indicating complete absorption of the drug after po administration. NEF, HO-NEF, and p-HO-NEF accounted for approximately 37% and 12% of the plasma AUC for total radioactivity following i.v. and po administration, respectively. The total urinary (28%) and fecal (61%) recovery after i.v. or po administration was approximately 90% of the dose within 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Shukla
U A
UA
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13221.
Marathe
P H
PH
Pittman
K A
KA
Barbhaiya
R H
RH
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D004285:Dogs; D005243:Feces / Q000737:chemistry; D007262:Infusions, Intravenous; D008297:Male; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000928:Antidepressive Agents; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D014230:Triazoles; C051752:nefazodone