Pharmacokinetics of nefazodone following multiple escalating oral doses in the dog.
The single and multiple dose pharmacokinetics of nefazodone (NEF) were investigated in a dose-escalating study in which 4 beagle dogs (weighing approximately 10 kg) were orally administered 100 mg nefazodone hydrochloride on days 1-7, 500 mg on days 8-14 and 1000 mg on days 15-20 once daily. Serial blood samples were collected over a 24 h period following administration of the first (day 1) and last (day 7) doses for the 100 mg/day dose and the last dose for the 500 (day 14) and 1000 mg/day (day 20) doses. Blood samples were also collected for trough level (Cmin) determination on the morning of the 5th, 6th and 7th day of 100 and 500 mg/day dosing regimens and the 3rd, 5th and 6th day of 1000 mg/day regimen. Plasma was analyzed for NEF and 3 metabolites [hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and p-hydroxynefazodone (p-HO-NEF)] by a validated HPLC assay. There were no significant differences between the 100 mg single and 100 mg/day multiple dose pharmacokinetic parameters for NEF, HO-NEF and mCPP. However, for p-HO-NEF, single dose elimination half life (T1/2) and area under the plasma concentration-time curve (AUC) extended to infinity were significantly smaller (P < or = 0.05) than the multiple dose T1/2 and AUCTAU, respectively. Based on Cmin data, steady state was reached by the 5th day of 500 mg/day and 1000 mg/day multiple dosing. Mean multiple dose AUCTAU values for NEF increased in a 1:9:26 ratio for a 1:5:10 increase in dose. Due to extensive variability and small number of animals used in the study, the statistical analysis indicated that AUCTAU values were dose-proportional. However, metabolite formation decreased significantly with increasing dose as indicated by AUCTAU ratios for metabolite:NEF. These data suggest that NEF exhibits nonlinear pharmacokinetics within 100-1000 mg/kg dose range in dogs.
Shukla
U A
UA
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13221.
Kaul
S
S
Marathe
P H
PH
Pittman
K A
KA
Barbhaiya
R H
RH
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006900:Hydroxylation; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000928:Antidepressive Agents; D010879:Piperazines; D014230:Triazoles; C051752:nefazodone; C015068:1-(3-chlorophenyl)piperazine