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Influence of hepatic impairment on the pharmacokinetics of nefazodone and two of its metabolites after single and multiple oral doses
Author(s) -
Ferry N.,
Bernard N.,
Cuisinaud G.,
Rougier P.,
Trepo C.,
Sassard J.
Publication year - 1994
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1994.tb00827.x
Subject(s) - nefazodone , pharmacokinetics , chemistry , metabolite , pharmacology , medicine , endocrinology , receptor , serotonin , fluoxetine
Summary— The pharmacokinetics of nefazodone, a new antidepressant, and two of its 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 mild ( n = 13) or severe ( n = 6) hepatic impairment. All subjects were classified according to their dextromethorphan oxidation capacity. In healthy volunteers, nefazodone was rapidly absorbed after which the plasma concentrations declined with an apparent elimination half‐life ranging from 2.7 ± 1.7 h to 10.2 ± 4.4 h according to the dosage. Hydroxynefazodone 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 disproportionately longer half‐life and more markedly increased C max and AUC 0–48 which was observed with dosage and treatment duration, and moreover AUC 0–12 at steady state significantly higher ( P < 0.05) than AUC 0–∞ after single dose demonstrated the non‐linearity of the pharmacokinetics of nefazodone and hydroxynefazodone. The constant molar AUC 0–48 hydroxy‐nefazodone/nefazodone ratio (0.32 ± 0.04) and the close correlation ( r 2 = 0.95) between kinetic parameters of nefazodone and hydroxynefazodone suggest that nefazodone hydroxylation is not a saturable process. The kinetics of nefazodone and metabolites were significantly affected by severe but not by mild liver insufficiency. As a consequence, on a pharmacokinetic basis nefazodone should be used with caution in severely hepatic impaired patients.