SINGLE AND MULTIPLE-DOSE PHARMACOKINETICS OF NEFAZODONE IN SUBJECTS CLASSIFIED AS EXTENSIVE AND POOR METABOLIZERS OF DEXTROMETHORPHAN

1 The single and multiple dose pharmacokinetics of nefazodone (NEF) an d its active metabolites hydroxynefazodone (HO-NEF) and m-chlorophenyl piperazine (mCPP) were evaluated in subjects classified as extensive m etabolizers (EM) or poor metabolizers (PM) of dextromethorphan. 2 In a parallel design study, 10 subjects from each phenotype received eithe r 50 mg or 200 mg oral doses of NEF as single doses on Day 1 and multi ple (twice daily) doses on Days 12-22. 3 Serial plasma and urine sampl es were collected at specified time intervals after dosing on Days 1, 16, 18, 20 and 22. Plasma samples were analyzed for NEF, HO-NEF and mC PP. Urine samples were analyzed for mCPP and its metabolite p-hydroxy- mCPP (p-HO-mCPP) before and after hydrolyzing the samples with beta-gl ucuronidase. 4 For the 200 mg dose group, the single dose plasma resul ts showed no significant differences in pharmacokinetic parameters for NEF and HO-NEF in EM compared with PM subjects. However, for mCPP, C- max was 89 ng ml(-1) in the PM subjects compared with 44 ng ml(-1) in the EM subjects, AUC was higher in the PM than EM subjects (1642 ng ml (-1) h and 412 ng ml(-1) h, respectively), and mCPP elimination half-l ife increased from 6.1 h in the EM subjects to 16.4 h in the PM subjec ts. Upon multiple dosing, plasma levels for NEF and all metabolites re ached steady state within 3 days of dosing in both groups of subjects. Steady state pharmacokinetic parameters for NEF and HO-NEF in EM and PM subjects were not significantly different. The steady state C-max a nd AUC values for mCPP in the PM subjects were 182 ng ml(-1) and 1706 ng ml(-1) h, respectively, compared with 49.6 ng ml(-1) and 182 ng ml( -1) h in the EM subjects. 5 The cumulative urinary excretion of mCPP a nd p-HO-mCPP was different for EM and PM subjects. Excretion of total mCPP and total p-HO-mCPP was approximately four-fold lower and five-fo ld higher, respectively, in the EM subjects than PM subjects. 6 These results indicate that the conversion of mCPP to p-HO-mCPP is attributa ble to metabolism by cytochrome P450 2D6. The differences in mCPP phar macokinetic parameters in PM subjects did not affect the time required for NEF and its metabolites to attain steady state or the number of a dverse experiences in either group of subjects. Based on the results o f this study, NEF may be dosed to EM and PM patients without regard to their cytochrome P450 2D6 phenotype.