Regioselectivity and Substrate Concentration-dependency of Involvement of the CYP2D Subfamily in Oxidative Metabolism of Amitriptyline and Nortriptyline in Rat Liver Microsomes

Author:

Masubuchi Yasuhiro1,Iwasa Takashi1,Fujita Shoichi2,Suzuki Tokuji1,Horie Toshiharu1,Narimatsu Shizuo1

Affiliation:

1. Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263

2. Department of Toxicology, Faculty of Veterinary Medicine, Hokkaido University, North 18, West 9, North Ward, Sapporo 060, Japan

Abstract

Abstract Kinetic analysis of the metabolism of amitriptyline and nortriptyline using liver microsomes from Wistar rats showed that more than one enzyme was involved in each reaction except for monophasic amitriptyline N-demethylation. The Vmax values particularly in the high-affinity sites for E-10-hydroxylation of both drugs were larger than those for Z-10-hydroxylations. Their E- and Z-10-hydroxylase activities in Dark-Agouti rats, which are deficient for CYP2D1, were significantly lower than those in Wistar rats at a lower substrate concentration (5 μM). The strain difference was reduced at a higher substrate concentration (500 μM). A similar but a smaller strain difference was also observed in nortriptyline N-demethylase activity, and a pronounced sex difference (male > female) was observed in N-demethylation of both drugs in Wistar and Dark-Agouti rats. The reactions with the strain difference were inhibited concentration-dependently by sparteine, a substrate of the CYP2D subfamily, and an antibody against a CYP2D isoenzyme. The profiles of these decreased metabolic activities corresponded to that of the lower metabolic activities in Dark-Agouti rats. These results indicated that a cytochrome P450 isozyme in the CYP2D subfamily was involved in E- and Z- 10-hydroxylations of amitriptyline and nortriptyline in rat liver microsomes as a major isozyme in a low substrate concentration range. It seems likely that the CYP2D enzyme contributes to nortriptyline N-demethylation.

Funder

Japan Research Foundation for Clinical Pharmacology

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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