Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin

Abstract

Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 × 10^-5 ) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 µM, whereas allopurinol showed no inhibition with concentrations up to 200 µM. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects.

Figure 1

Study design. In a randomized crossover study, 10 healthy individuals ingested as pretreatment either placebo, 120 mg febuxostat, or 300 mg allopurinol once daily at 8 am. On day 6 of each phase, the participants ingested 10 mg of rosuvastatin at 9 am. There was a washout period of 2 weeks between the last day of pretreatment and the start of the pretreatment in the next phase.

Figure 2

The effect of allopurinol and febuxostat on the plasma concentrations of rosuvastatin. Ten healthy volunteers ingested as pretreatment either 300 mg allopurinol on days 1–7 (a), or 120 mg febuxostat on days 4–7 (b), or placebo. Rosuvastatin 10 mg was administered 1 hour after the administration of pretreatment on day 6 of each of the three phases. Data are geometric means with 90% confidence interval. For clarity, some error bars have been omitted. Insets depict the same data on a semilogarithmic scale.

Figure 3

The individual rosuvastatin area under the plasma concentration‐time curve from zero to infinity (AUC_0–∞) values in healthy volunteers after the administration of 10 mg rosuvastatin in a crossover study during placebo, allopurinol, and febuxostat phases.

Figure 4

The effect of febuxostat and allopurinol on the BCRP‐mediated transport of rosuvastatin in the vesicular transport assay. BCRP‐expressing membrane vesicles were incubated in the presence of rosuvastatin and febuxostat (a) or allopurinol (b). The ATP‐dependent transport of rosuvastatin in the absence of test compounds was set as 100%. Data are means ± SD (n = 6).