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. Gout is an increasingly common condition, and the most common form of inflammatory arthritis in developed countries. The main cause of gout is chronic hyperuricemia. Elevated serum uric acid concentration leads to accumulation of monosodium urate in joints, where urate crystals cause an extremely painful inflammatory arthritis and recurrent gout flares. Risk factors for gout include obesity, renal failure, genetic variability, diet, medications, such as diuretics, and excessive consumption of alcohol. 1-4 The increasing prevalence rates of gout worldwide are concordant with the role of lifestyle in its development. Allopurinol is the first-line treatment of chronic hyperuricemia and gout. It is used as a long-term medication to prevent attacks of gout and avoid permanent damage to the joints. Being a nonselective inhibitor of the xanthine oxidase enzyme, allopurinol prevents biotransformation of

Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout

“…On the other hand, among the clinically-used inhibitors for the production of uric acid (i.e., allopurinol, febuxostat, and topiroxostat), only febuxostat, to the best of our knowledge, strongly and clinically inhibits ABCG2 function as a urate transporter [ 35 ]. This is also supported by a recent clinical study that showed orally-administered febuxostat inhibits intestinal ABCG2 in humans [ 46 ]. In this context, the efficacy of febuxostat as an SUA-lowering drug can be partially blocked by ABCG2 inhibition, except in cases of completely null ABCG2 function.…”

Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2

“…In the past, probenecid was used to sustain the serum concentration of penicillin, an OAT1/3 substrate 28 . Recently, it was reported that febuxostat increased the blood concentration of methotrexate and rosuvastatin, which are ABCG2 substrates 29 , 30 . In the present study, probenecid and benzbromarone should have functioned as OAT1/3 inhibitors and febuxostat as an ABCG2 inhibitor.…”

The Encapsulation of Febuxostat into Emulsomes Strongly Enhances the Cytotoxic Potential of the Drug on HCT 116 Colon Cancer Cells

“…Recently, several studies have been conducted to examine the FBX anti-cancer activity [ 16 , 42 , 43 ], with particular regard to its ability to enhance cancer cells death via apoptosis and decrease the chemotherapy resistance, then representing a promising candidate for cancer treatment. Additionally, based on its ability to reduce uric acid production in the body, this drug has been used for the treatment of tumor lysis syndrome, a metabolic impairment that arises in cancer patients [ 15 , 44 ].…”