Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin.
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Lehtisalo M, Keskitalo JE, Tornio A, Lapatto-Reiniluoto O, Deng F, Jaatinen T, Viinamaki J, Neuvonen M, Backman JT, Niemi M
Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin.
Clin Transl Sci. 2020 Nov;13(6):1236-1243. doi: 10.1111/cts.12809. Epub 2020 May 26.
- PubMed ID
- 32453913 [ View in PubMed]
- 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 x 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 microM, whereas allopurinol showed no inhibition with concentrations up to 200 microM. 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Febuxostat ATP-binding cassette sub-family G member 2 Protein Humans NoInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAbemaciclibFebuxostat The excretion of Abemaciclib can be decreased when combined with Febuxostat. AfatinibFebuxostat The excretion of Afatinib can be decreased when combined with Febuxostat. AllopurinolFebuxostat The excretion of Allopurinol can be decreased when combined with Febuxostat. ApixabanFebuxostat The excretion of Apixaban can be decreased when combined with Febuxostat. BinimetinibFebuxostat The excretion of Binimetinib can be decreased when combined with Febuxostat.