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

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dc.contributor.author Lehtisalo, Minna
dc.contributor.author Keskitalo, Jenni E.
dc.contributor.author Tornio, Aleksi
dc.contributor.author Lapatto-Reiniluoto, Outi
dc.contributor.author Deng, Feng
dc.contributor.author Jaatinen, Taina
dc.contributor.author Viinamäki, Jenni
dc.contributor.author Neuvonen, Mikko
dc.contributor.author Backman, Janne T.
dc.contributor.author Niemi, Mikko
dc.date.accessioned 2021-02-04T08:37:01Z
dc.date.available 2021-02-04T08:37:01Z
dc.date.issued 2020-11
dc.identifier.citation 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
dc.identifier.other PURE: 138664674
dc.identifier.other PURE UUID: 1a242be1-3daa-4314-bfd3-44e2493847db
dc.identifier.other WOS: 000535322300001
dc.identifier.other ORCID: /0000-0002-9577-2788/work/88204111
dc.identifier.other ORCID: /0000-0001-5713-5692/work/88205428
dc.identifier.other ORCID: /0000-0002-9173-6923/work/106339714
dc.identifier.uri http://hdl.handle.net/10138/325866
dc.description.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. en
dc.format.extent 8
dc.language.iso eng
dc.relation.ispartof Clinical and translational science
dc.rights cc_by_nc
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject ABCG2 BCRP
dc.subject TRANSPORTER
dc.subject GOUT
dc.subject ELTROMBOPAG
dc.subject OATP1B1
dc.subject RISK
dc.subject 3111 Biomedicine
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin en
dc.type Article
dc.contributor.organization INDIVIDRUG - Individualized Drug Therapy
dc.contributor.organization Department of Clinical Pharmacology
dc.contributor.organization Research Programs Unit
dc.contributor.organization University of Helsinki
dc.contributor.organization Helsinki University Hospital Area
dc.contributor.organization HUSLAB
dc.contributor.organization Janne Backman / Principal Investigator
dc.contributor.organization Clinicum
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1111/cts.12809
dc.relation.issn 1752-8054
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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