PHARMACOKINETICS OF NEFAZODONE IN THE DOG FOLLOWING SINGLE ORAL-ADMINISTRATION

The pharmacokinetics of nefazodone (NEF) and two of its pharmacologically active metabolites viz hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were determined following single oral administration of 100, 200 and 400 mg NEF to 6 beagle dogs in a three-way crossover study. Blood samples were collected for 48 h and plasma was analyzed for NEF, HO-NEF and mCPP by a validated HPLC assay. NEF was rapidly absorbed after oral administration. C(max) values for all three compounds and AUC(inf) values for HO-NEF and mCPP were dose-proportional; AUC(inf) values for NEF were dose-linear but not dose-proportional. The T1/2 values for NEF and HO-NEF following the 400 mg dose were significantly greater than those for the 100 mg dose. No differences in mCPP T1/2 were observed among the doses. The C(max) and AUC(inf) ratios for metabolite:NEF were about 2-fold lower for the 200 and 400 mg doses than those observed for the 100 mg dose. However, due to extensive variability, the ratios for three doses were not significantly different based on statistical analysis. Overall, these data suggest die pharmacokinetics of NEF are dose-dependent in the beagle dog. Statistical significance for dose-dependency for many of the pharmacokinetic parameters could not be demonstrated due to high variability associated with the plasma concentration vs time profiles.