期刊
DRUG METABOLISM AND PHARMACOKINETICS
卷 27, 期 3, 页码 349-353出版社
JAPANESE SOC STUDY XENOBIOTICS
DOI: 10.2133/dmpk.DMPK-11-NT-068
关键词
chlorothiazide; absorption; ABCG2 substrate; vesicular transport; MDCKII-BCRP; Caco-2; probe for regulatory studies
资金
- Hungarian National Office for Research and Technology [XTTPSRT1, GOP 1.3.2.]
We are showing that chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that chlorothiazide is transported by ABCG2 with a K-m value of 334.6 mu M and does not interact with ABCB1 or ABCC2. The chlorothiazide ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting chlorothiazide bioavailability in humans.
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