Abstract
ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs.
Highlights
ATP-binding cassette transporter G2 (ABCG2) is a member of ABC transporter superfamily and is recognized as one of the most important drug efflux transporters (Giacomini et al, 2010; Lee et al, 2015; Mao and Unadkat, 2015)
ABCG2 often lowers the bioavailability of other drugs such as rosuvastatin (Keskitalo et al, 2009; Tomlinson et al, 2010), which is widely used to treat dyslipidemia, and sunitinib (Mizuno et al, 2010), a multi-targeted receptor tyrosine kinase inhibitor used in cancer chemotherapy
We revealed that febuxostat could enhance the intestinal absorption of sulfasalazine, a well-known ABCG2 substrate in both humans (Yamasaki et al, 2008) and mice (Zaher et al, 2006), by using WT and Abcg2 KO mice
Summary
ATP-binding cassette transporter G2 (ABCG2) is a member of ABC transporter superfamily and is recognized as one of the most important drug efflux transporters (Giacomini et al, 2010; Lee et al, 2015; Mao and Unadkat, 2015). ABCG2 is expressed in cancer tissues and in numerous normal tissues such as the small intestine and kidney (Doyle et al, 1998). ABCG2 regulates the pharmacokinetics and efficacy of its substrate drugs. ABCG2 is involved in the efflux of its substrates from the epithelial cells into the intestinal lumen, which could lower their bioavailability. ABCG2 often lowers the bioavailability of other drugs such as rosuvastatin (Keskitalo et al, 2009; Tomlinson et al, 2010), which is widely used to treat dyslipidemia, and sunitinib (Mizuno et al, 2010), a multi-targeted receptor tyrosine kinase inhibitor used in cancer chemotherapy. The intestinal inhibition of ABCG2 would be an effective strategy to improve the efficacy of such drugs by enhancing their bioavailability. The clinical inhibition of ABCG2 may be beneficial, there are currently no appropriate drugs and candidates to inhibit ABCG2
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