N. Ferry et al., INFLUENCE OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF NEFAZODONEAND 2 OF ITS METABOLITES AFTER SINGLE AND MULTIPLE ORAL DOSES, Fundamental and clinical pharmacology, 8(5), 1994, pp. 463-473
The pharmacokinetics of nefazodone, a new antidepressant, and two of i
ts active metabolites, hydroxynefazodone and m-chlorophenylpiperazine,
were determined after single and repeated oral escalating doses of 50
, 100 and 200 mg, in healthy volunteers (n = 13) and patients with mil
d (n = 13) or severe (n = 6) hepatic impairment. All subjects were cla
ssified according to their dextromethorphan oxidation capacity. In hea
lthy volunteers, nefazodone was rapidly absorbed after which the plasm
a concentrations declined with an apparent elimination half-life rangi
ng from 2.7 +/- 1.7 h to 10.2 +/- 4.4 h according to the dosage. Hydro
xynefazodone appeared rapidly in plasma and its time-course (half-life
ranging 1.4 +/- 0.9 h to 6.5 +/- 1.6 h) paralleled that of nefazodone
, while mCPP showed low and variable concentrations. The disproportion
ately longer half-life and more markedly increased C-max and AUC(0-48)
which was observed with dosage and treatment duration, and moreover A
UC(0-12) at steady state significantly higher (P < 0.05) than AUC(0-in
finity) after single dose demonstrated the non-linearity of the pharma
cokinetics of nefazodone and hydroxynefazodone. The constant molar AUC
(0-48) hydroxy-nefazodone/nefazodone ratio (0.32 +/- 0.04) and the clo
se correlation (r(2) = 0.95) between kinetic parameters of nefazodone
and hydroxynefazodone suggest that nefazodone hydroxylation is not a s
aturable process. The kinetics of nefazodone and metabolites were sign
ificantly affected by severe but not by mild liver insufficiency. As a
consequence, on a pharmacokinetic basis nefazodone should be used wit
h caution in severely hepatic impaired patients.