bcrp - publications

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1. Br J Pharmacol. 2012 Feb 2. doi: 10.1111/j.1476-5381.2012.01887.x. [Epub ahead of

Pharmacokinetic interaction study of sulfasalazine in healthy subjects and the
impact of curcumin as an in vivo inhibitor of BCRP.

Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, Fukizawa S, Morimoto
N, Ieiri I, Morishita M, Sumita K, Mayahara H, Fujita T, Maeda K, Sugiyama Y.

University of Tokyo, Tokyo, Japan (H.K., C. W., S.F., K.M., Y.S.)Osaka
Pharmacology Clinical Research Hospital, Osaka, Japan (H. F., S.Y.)Nishiwaki
Laboratory, JCL Bioassay Corporation, Hyogo, Japan (A.S.)Association for
Promoting Drug Development, Tokyo, Japan (A.I.)Graduate School of Pharmaceutical
Sciences, Kyushu University, Fukuoka, Japan. (I.I.)Hoshi University, Tokyo, Japan
(N.M., M.Mo, K.T.) Rabiton, Osaka, Japan (M.S.)InCROM, Osaka, Japan
(H.M.)Ritsumeikan University, Shiga, Japan (T.F.).

Background and purpose.  An ABC transporter BCRP/ABCG2 limits oral
bioavailability of sulfasalazine. This study aimed to examine the effect of
curcumin, the principal curcuminoid of turmeric, on oral bioavailability of
microdose and therapeutic dose of sulfasalazine in humans. Experimental
approach.  Effect of curcumin was examined for the ATP-dependent sulfasalazine
uptake by hBCRP expressing membrane vesicles, and for the oral bioavailability of
sulfasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects
received an oral dose of sulfasalazine suspension (100µg) or tables (2g) alone or
after oral dose of curcumin tablets (2g). To investigate the effect of OATP2B1,
an influx transporter in the intestine, on sulfasalazine, its uptake was
determined in the cDNA transfectants. Key Results.  Curcumin is a potent hBCRP
inhibitor in vitro (Ki 0.70 ± 0.41µM). Curcumin increased the AUC(0-8 ) of plasma
sulfasalazine concentrations 8-fold in wild-type mice at 300 and 400 mg/kg, but
not in Bcrp(-/-) mice. Curcumin could increase AUC(0-24) of plasma sulfasalazine
concentrations, 2.0 and 3.2-fold, at the microdose and therapeutic dose,
respectively, in humans. Nonlinearity of the dose-exposure relationship was
observed between microdose and therapeutic dose of sulfasalazine. Sulfasalazine
is an OATP2B1 substrate (K(m) 1.7 ± 0.3µM). Its linear index (Dose/K(m) ) at the
therapeutic dose was high enough to consider the possibility of OATP2B1
saturation. Conclusions and Implications.  Curcumin can be used to investigate
impact of BCRP on oral bioavailability of drugs in humans. Besides the limited
dissolution, OATP2B1 saturation is suggested as a mechanism underlying the
non-linearity in the dose-exposure relationship of sulfasalazine. © 2012 The
Authors. British Journal of Pharmacology © 2012 The British Pharmacological

© 2012 The Authors. British Journal of Pharmacology © 2012 The British
Pharmacological Society.

PMID: 22300367 [PubMed - as supplied by publisher]