Regioselectivity and substrate concentration-dependency of involvement of the CYP2D subfamily in oxidative metabolism of amitriptyline and nortriptyline in rat liver microsomes

Yasuhiro Masubuchi, Takashi Iwasa, Shoichi Fujita, Tokuji Suzuki, Toshiharu Horie, Shizuo Narimatsu

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 V(max) 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.

Original languageEnglish
Pages (from-to)925-929
Number of pages5
JournalJournal of Pharmacy and Pharmacology
Volume48
Issue number9
Publication statusPublished - Sep 1996
Externally publishedYes

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Nortriptyline
Amitriptyline
Liver Microsomes
Hydroxylation
Isoenzymes
Wistar Rats
N Demethylating Oxidoreductases
Sparteine
Metabolome
Enzymes
Mixed Function Oxygenases
Sex Characteristics
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Antibodies
Dasyproctidae

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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Regioselectivity and substrate concentration-dependency of involvement of the CYP2D subfamily in oxidative metabolism of amitriptyline and nortriptyline in rat liver microsomes. / Masubuchi, Yasuhiro; Iwasa, Takashi; Fujita, Shoichi; Suzuki, Tokuji; Horie, Toshiharu; Narimatsu, Shizuo.

In: Journal of Pharmacy and Pharmacology, Vol. 48, No. 9, 09.1996, p. 925-929.

Research output: Contribution to journalArticle

Masubuchi, Yasuhiro ; Iwasa, Takashi ; Fujita, Shoichi ; Suzuki, Tokuji ; Horie, Toshiharu ; Narimatsu, Shizuo. / Regioselectivity and substrate concentration-dependency of involvement of the CYP2D subfamily in oxidative metabolism of amitriptyline and nortriptyline in rat liver microsomes. In: Journal of Pharmacy and Pharmacology. 1996 ; Vol. 48, No. 9. pp. 925-929.
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