Hyperuricemia is defined as SUA levels > 7.0 mg/dL ( Yamanaka, 2011) and is associated with some diseases such as metabolic syndrome, hypertension and gout ( Richette et al., 2014). Recently, we and other research groups have independently found that ABCG2 is a physiologically important regulator of urate ( Matsuo et al., 2009 Woodward et al., 2009 Ichida et al., 2012 Matsuo et al., 2014) as well as URAT1, a major component of the urate reabsorption system in the kidney and a target of hyperuricemia therapy ( Enomoto et al., 2002). Therefore, the clinical inhibition of ABCG2 may be beneficial, although there are currently no appropriate drugs and candidates to inhibit ABCG2. The intestinal inhibition of ABCG2 would be an effective strategy to improve the efficacy of such drugs by enhancing 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. For instance, the plasma concentrations ( Yamasaki et al., 2008) and efficacy ( Wiese et al., 2014) of orally administered sulfasalazine, an antirheumatic drug, are modulated by the function of ABCG2, which appears to be affected by at least one SNP in its cognate gene ABCG2 in humans. In the small intestine, ABCG2 is involved in the efflux of its substrates from the epithelial cells into the intestinal lumen, which could lower their bioavailability. Accumulating evidence indicates that ABCG2 plays a pivotal role as a gatekeeper against xenobiotics ( Jonker et al., 2002 Giacomini et al., 2010).ĪBCG2 regulates the pharmacokinetics and efficacy of its substrate drugs. ABCG2 is expressed not only in cancer tissues but also in numerous normal tissues such as the small intestine and kidney ( Doyle et al., 1998). Following the identification of the expression of this protein as the cause of acquired multidrug resistance (MDR) in breast cancer cell lines, ABCG2 has been termed breast cancer resistance protein ( Doyle et al., 1998). 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.ĪTP-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). These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. 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. 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.
The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2.
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.
Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function.
Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. 3Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, JapanĪTP-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.2Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan.1Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.Hiroshi Miyata 1†, Tappei Takada 1*†, Yu Toyoda 1†, Hirotaka Matsuo 2, Kimiyoshi Ichida 3 and Hiroshi Suzuki 1
0 kommentar(er)
