In vivo inhibition of CYP3A-mediated midazolam metabolism by anchusan in rats.

Abstract:

:Cytochrome P450 (CYP)-mediated drug interactions caused by Kampo medicine have not been investigated sufficiently. The current study was conducted to reveal the effect of anchusan, a commonly used Kampo formula for gastrointestinal disease, on CYP3A-mediated drug metabolism in rats. The pharmacokinetics of midazolam (MDZ) was investigated after the single or one-week administration of anchusan (500 mg/kg) to evaluate its inhibitory and inducible effect on CYP3A, respectively. MDZ was administrated 16 h after the last anchsan treatment in the multiple dose study, while their intervals were 2 or 16 h in the single dose study. Unexpectedly, the multiple-pretreatment of anchusan increased the AUC of MDZ by 2.4-fold rather than decreasing it, and the CYP3A contents and activities were unchanged in hepatic and intestinal microsomes of these rats. In contrast, no significant inhibitory effects on MDZ metabolism were observed by the single anchusan pretreatment. In vitro study showed that the preincubation of anchusan and some of its component extracts with rat liver microsomes reduced CYP3A activity in a time- and NADPH-dependent manner. These results suggested that anchusan increased the serum MDZ concentration in rats, at least in part, by the time-dependent inhibition of CYP3A.

journal_name

J Pharmacol Sci

authors

Saito Y,Nishimura Y,Kurata N,Iwase M,Aoki K,Yasuhara H

doi

10.1254/jphs.10277fp

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

399-407

issue

3

eissn

1347-8613

issn

1347-8648

pii

JST.JSTAGE/jphs/10277FP

journal_volume

115

pub_type

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