Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism ofE- andZ-doxepin
作者:
V. Haritos,
H. Ghabrial,
J. Ahokas,
M. Ching,
期刊:
Pharmacogenetics
(OVID Available online 2000)
卷期:
Volume 10,
issue 7
页码: 591-603
ISSN:0960-314X
年代: 2000
出版商: OVID
关键词: doxepin;CYP2D6;human liver microsomes;stereoselective;metabolism
数据来源: OVID
摘要:
The tricyclic antidepressant, doxepin, is formulated as an irrational mixture of E (trans) and Z (cis) stereoisomers (85% : 15%). We examined the stereoselective metabolism of doxepinin vitro, with the use of human liver microsomes, recombinant CYP2D6 and gas chromatography-mass spectrometry. In human liver microsomes over the concentration range 5–1500 μM, the rate ofZ-doxepinN-demethylation exceeded that ofE-doxepin above 100 μM in two of three livers. Eadie–Hofstee plots were curvilinear indicating the involvement of several enzymes inN-demethylation. Coincubation of doxepin with 7,8-naphthoflavone and ketoconazole reduced the rates ofN-demethylation ofE- andZ-doxepin by 30–50% and 40–60%, respectively, suggesting the involvement of CYP1A and CYP3A4, whilst quinidine had little effect onN-demethylation. In contrast, doxepin hydroxylation was exclusively stereospecific;E-doxepin andE-N-desmethyldoxepin were hydroxylated with high affinity in liver microsomes and by recombinant CYP2D6 (Kmin the range of 5–8 μM), but there was no evidence ofZ-doxepin hydroxylation. In ‘metabolic consumption’ experiments with liver microsomes (having measurable CYP2D6 activity) and initial substrate concentration of 1 μM, the consumption ofE-doxepin was greater (P<0.05,n= 5) than that ofZ-doxepin. Quinidine inhibited the consumption ofE-doxepin but did not affect the consumption ofZ-doxepin. WithN-desmethyldoxepin, quinidine inhibited the consumption ofE-N-desmethyldoxepin whereasZ-N-desmethyldoxepin appeared to be a terminal oxidative metabolite. In summary, CYP2D6 is a major oxidative enzyme in doxepin metabolism; predominantly catalysing hydroxylation with an exclusive preference for theE-isomers. The relatively more rapid metabolism ofE-isomeric forms, and the limited metabolic pathways for theZ-isomers may explain the apparent enrichment ofZ-N-desmethyldoxepin that is observedin vivo.
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