A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin.

Abstract:

:CYP2C9 is mainly responsible for the metabolic clearance of phenytoin and (S)-warfarin. We have shown previously that mutations in the CYP2C9 gene are associated with diminished metabolism of (S)-warfarin, and so we have now studied the metabolism of phenytoin to its primary inactive metabolite, (S)-pHPPH, by these mutant enzymes. Kinetic parameters were determined for (S)-pHPPH formation using recombinant CYP2C9 variants purified from insect cells. The data demonstrate that the CYP2C9*3 gene product retains only 4-6% of the metabolic efficiency of the wild-type protein, CYP2C9*1, towards phenytoin and (S)-warfarin. Consequently, we suggest that homozygous expression of CYP2C9*3 may represent a common genetic basis for (apparently) idiosyncratic toxicities that have been reported for these two low therapeutic index drugs.

journal_name

Epilepsy Res

journal_title

Epilepsy research

authors

Rettie AE,Haining RL,Bajpai M,Levy RH

doi

10.1016/s0920-1211(99)00017-0

subject

Has Abstract

pub_date

1999-07-01 00:00:00

pages

253-5

issue

3

eissn

0920-1211

issn

1872-6844

pii

S0920121199000170

journal_volume

35

pub_type

杂志文章
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    pub_type: 临床试验,杂志文章,多中心研究,随机对照试验

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    更新日期:2013-03-01 00:00:00

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    doi:10.1016/j.eplepsyres.2006.02.007

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