Influence of the mephenytoin oxidation polymorphism on the steady-state plasma concentrations of imipramine and its active metabolite, desipramine, in 32 Japanese psychiatric patients

• Published in: Japanese Journal of Pharmacology 1993, Vol.61 (suppl.2), p.318-318
• Main Authors: Koyama, Eriko, Tanaka, Takeshi, Morinobu, Shigeru, Kawakatsu, Shinobu, Totsuka, Shirou, Chiba, Kan, Ishizaki, Takashi
• Format: Article
• Language: eng ; jpn
• ISSN: 0021-5198
• DOI: 10.1016/S0021-5198(19)39694-5

About 22% of Japanese are poor metabolizers(PMs) for 4'-hy-droxylation of S-mephenytoin (MP). To study if this type of oxidation polymorphism would influence on the steady-state plasma concentrations of imipramine (IMI) and its active metabolite, desipramine (DMI), in Japanese depressive patients, their plasma concentrations at steady-state were assayed by HPLC with electrochemical detection over a 12-hr dosing interval in 5 patients with PM phenotype and 27 patients with extensive metabolizer (EM) phenotype of MP during the IMI therapy (0.39-1.39mg/kg/day). All of them were phenotyped with metoprolol as EMs of the debrisoquin type oxidation. The mean IMI and IMI + DMI concentrations corrected for the mg/kg-dose were 2.3 and 1.8 times greater in the PMs than in the EMs of MP (p＜0.001). In addition, the mean mg/kg-dose-corrected plasma concentarations of IMI and IMI+DMI correlated (r_s = -0.605 and -0.550, p＜0.005, respectively) with the amount of 8-hr urinary excretion of 4-hydroxy MP. The demethylation index, defined as plasma IMI/DMI concentration ratio, also correlated (r_s =-0.498, p ＜ 0.005) with the 8-hr urinary excretion of 4-hydroxy MP. Results suggest that the demethylation activity of IMI to DMI cosegregates with that of MP oxidation in our patients with depression. Thus, the MP oxidation polymorphism would be an important determinant for the steady-state plasma concentarations of IMI and IMI+DMI during the IMI therapy in Japanese psychiatric patients.