Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

Hiroshi Miyata, Tappei Takada, Yu Toyoda, Hirotaka Matsuo, Kimiyoshi Ichida, Hiroshi Suzuki, Hiroshi Miyata, Tappei Takada, Yu Toyoda, Hirotaka Matsuo, Kimiyoshi Ichida, Hiroshi Suzuki

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.

Keywords: BCRP; URAT1; allopurinol; benzbromarone; bioavailability; drug repositioning; drug-drug interactions; topiroxostat.

Figures

FIGURE 1
FIGURE 1
Effect of serum uric acid (SUA)-affecting drugs on the urate transport activity of ABCG2.(A) Expression of ABCG2 on membrane vesicles. Membrane vesicles (5 μg) were subjected to western blot analysis using a BXP-21, an anti-ABCG2 or anti-Na+/K+-ATPase antibody. (B) Time-dependent increase in the urate transport by ABCG2. The urate transport into membrane vesicles was measured at the indicated periods with (closed) or without (open) ATP. Values are expressed as mean ± SD. (n = 3). (C) The urate transport activities of ABCG2 in the presence of each SUA-affecting drug. Concentrations of each drug are shown in Table 1. The urate transport into membrane vesicles was measured in the presence of each SUA-affecting drug for 10 min. Data are shown as the percentage of vehicle control (without drugs). Values are expressed as mean ± SD (n = 3).
FIGURE 2
FIGURE 2
Dose-dependent inhibition of ABCG2-mediated urate transport by serum uric acid (SUA)-affecting drugs. The urate transport activities were measured in the presence of the following drugs at the indicated concentrations for 10 min. (A) Losartan, (B) Fenofibrate, (C) Atorvastatin, (D) Cyclosporine, (E) Furosemide, (F) Tacrolimus, (G) Rosuvastatin, (H) Benzbromarone, (I) Topiroxostat, and (J) Febuxostat. Data are shown as the percentage of vehicle control (without drugs). Values are expressed as mean ± SD (n = 3).
FIGURE 3
FIGURE 3
Inhibition of mouse Abcg2 by febuxostat in vitro and in vivo.(A) Dose-dependent inhibition of mouse Abcg2 by febuxostat in vitro. The urate transport activities of mouse Abcg2 were measured in the presence of febuxostat at the indicated concentrations. Data are shown as the percentage of vehicle control (without febuxostat). Values are expressed as mean ± SD (n = 3). (B) Time-dependent changes in sulfasalazine plasma concentration with the pre-administration of febuxostat. Twenty minutes after the oral administration of febuxostat (n = 4) or vehicle (n = 7), sulfasalazine was orally administered to WT mice. The blood samples were collected at the indicated periods, and the plasma concentrations of sulfasalazine were determined using LC/MS/MS. Values are expressed as mean ± SEM. (C) AUC 0-120 min of sulfasalazine in WT and Abcg2 KO mice with or without pre-administration of febuxostat. Twenty minutes after the oral administration of febuxostat (n = 4 for both WT and Abcg2 KO) or vehicle (n = 7 and 5 for WT and Abcg2 KO, respectively), sulfasalazine was orally administered to WT and Abcg2 KO mice. The blood samples were collected at 15, 30, 60, 90, and 120 min and then the plasma concentrations of sulfasalazine were determined using LC/MS/MS. AUC 0-120 min was determined for each group using the well-used trapezoidal rule. Values are expressed as mean ± SEM. Statistical analyses for significant differences were performed using two-way ANOVA followed by Tukey–Kramer method; ∗p < 0.05 vs. vehicle control WT mice; N.S., not significantly different among groups.
FIGURE 4
FIGURE 4
Inhibitory effect of serum uric acid (SUA)-affecting drugs on the urate transport activities mediated by ABCG2 and URAT1.(A) Expression of FLAG-URAT1 on 293A cells. Whole cell lysates (30 μg) of transient FLAG-URAT1-expressing 293A cells were subjected to western blot analysis using anti-FLAG or anti-Na+/K+-ATPase antibody. (B) Time-dependent increase of urate transport into FLAG-URAT1-expressing 293A cells. Values are expressed as mean ± SD (n = 3). (C) Effects of each SUA-affecting drug on the urate transport activities of ABCG2 and URAT1. The urate transport activities of ABCG2 and URAT1 were evaluated in the presence of 3 μM of each SUA-affecting drug. Data are shown as the percentage of vehicle control (without drugs). Values are expressed as mean ± SD (n = 3). Individual data for each drug are shown in Supplementary Figure S1.
FIGURE 5
FIGURE 5
Summary of potential effects of inhibiting ABCG2 in vivo.(A) Schematic illustration of potential precautions and putative application of febuxostat as an ABCG2 inhibitor. (B) Schematic illustration of canceled out mechanism of benzbromarone, febuxostat and topiroxostat as SUA-lowering drugs. ALA, 5-aminolevulinic acid; Feb, febuxostat; Top, topiroxostat; Ben, benzbromarone.

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