Lehtisalo , M , Keskitalo , J E , Tornio , A , Lapatto-Reiniluoto , O , Deng , F , Jaatinen , T , Viinamäki , J , Neuvonen , M , Backman , J T & Niemi , M 2020 , ' Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin ' , Clinical and translational science , vol. 13 , no. 6 , pp. 1236-1243 . https://doi.org/10.1111/cts.12809
Title: | Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin |
Author: | Lehtisalo, Minna; Keskitalo, Jenni E.; Tornio, Aleksi; Lapatto-Reiniluoto, Outi; Deng, Feng; Jaatinen, Taina; Viinamäki, Jenni; Neuvonen, Mikko; Backman, Janne T.; Niemi, Mikko |
Contributor organization: | INDIVIDRUG - Individualized Drug Therapy Department of Clinical Pharmacology Research Programs Unit University of Helsinki Helsinki University Hospital Area HUSLAB Janne Backman / Principal Investigator Clinicum |
Date: | 2020-11 |
Language: | eng |
Number of pages: | 8 |
Belongs to series: | Clinical and translational science |
ISSN: | 1752-8054 |
DOI: | https://doi.org/10.1111/cts.12809 |
URI: | http://hdl.handle.net/10138/325866 |
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 mu M, whereas allopurinol showed no inhibition with concentrations up to 200 mu M. 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. |
Subject: |
DRUG-DRUG INTERACTION
HEPATIC-UPTAKE ABCG2 BCRP PHARMACOKINETICS TRANSPORTER GOUT ELTROMBOPAG OATP1B1 RISK ATORVASTATIN 3111 Biomedicine 3121 General medicine, internal medicine and other clinical medicine |
Peer reviewed: | Yes |
Rights: | cc_by_nc |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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