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夫西地酸抑制肝脏转运体和代谢酶:与他汀类药物联合使用时观察到临床药物相互作用的潜在原因。

Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration.

作者信息

Gupta Anshul, Harris Jennifer J, Lin Jianrong, Bulgarelli James P, Birmingham Bruce K, Grimm Scott W

机构信息

Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA

Drug Metabolism and Pharmacokinetics, Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.

出版信息

Antimicrob Agents Chemother. 2016 Sep 23;60(10):5986-94. doi: 10.1128/AAC.01335-16. Print 2016 Oct.

Abstract

Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP-mediated efflux (50% inhibitory concentration [IC50], ∼50 to 110 μM) and OATP1B1-mediated uptake (IC50, ∼4 to 35 μM) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is ∼4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 μM or 11 μM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, ∼17 to 195 μM). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins.

摘要

夫西地酸(FA)于20世纪60年代在许多欧洲和亚洲国家获批,由于其对耐甲氧西林金黄色葡萄球菌持续有效,重新引起了人们的关注。由于有报道称FA与他汀类药物合用时会发生横纹肌溶解,我们旨在阐明导致FA与他汀类药物发生药物相互作用的潜在分子机制。鉴于横纹肌溶解与他汀类药物暴露增加之间的关联,我们研究了参与各种他汀类药物处置的细胞色素P450(CYP)酶和转运蛋白是否受到FA的抑制。研究发现FA可抑制乳腺癌耐药蛋白(BCRP)和有机阴离子转运多肽1B1(OATP1B1),但不抑制P-糖蛋白(P-gp)。在过表达细胞系统中,FA在肠道和肝脏中可达到的临床相关浓度下(基于550mg口服剂量的FA,预期最大理论胃肠道浓度约为4mM,多次给药后肝脏入口处的最大总浓度或未结合浓度分别报告高达223μM或11μM),抑制了他汀类药物的BCRP介导的外排(半数抑制浓度[IC50],约50至110μM)和OATP1B1介导的摄取(IC50,约4至35μM)。同样,FA在人肝微粒体中抑制了他汀类药物的代谢(IC50,约17至195μM)。这些数据表明FA至少抑制了3种主要的处置途径(BCRP、OATP1B1和CYP3A),从而影响了几种他汀类药物的清除。我们证实FA通过I相代谢(主要通过CYP3A)消除;然而,也存在一些II相代谢(主要由尿苷二磷酸葡萄糖醛酸基转移酶1A1[UGT1A1]介导)。综上所述,这些数据为FA与他汀类药物合用时可能解释横纹肌溶解发生的分子机制提供了证据。

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本文引用的文献

4
A timely reminder about the concomitant use of fusidic acid with statins.
Clin Infect Dis. 2013 Jul;57(2):329-30. doi: 10.1093/cid/cit236. Epub 2013 Apr 15.
5
Population pharmacokinetics of fusidic acid: rationale for front-loaded dosing regimens due to autoinhibition of clearance.
Antimicrob Agents Chemother. 2013 Jan;57(1):498-507. doi: 10.1128/AAC.01354-12. Epub 2012 Nov 12.
6
[Rhabdomyolysis following the coprescription of atorvastatin and fusidic acid].
Rev Med Interne. 2013 Jan;34(1):39-41. doi: 10.1016/j.revmed.2012.09.006. Epub 2012 Oct 24.
7
Rhabdomyolysis after co-prescription of statin and fusidic acid.
BMJ. 2012 Oct 9;345:e6562. doi: 10.1136/bmj.e6562.
9
Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins.
Eur J Pharm Sci. 2012 Aug 30;47(1):244-55. doi: 10.1016/j.ejps.2012.04.003. Epub 2012 Apr 19.
10
Pharmacological actions of statins: a critical appraisal in the management of cancer.
Pharmacol Rev. 2012 Jan;64(1):102-46. doi: 10.1124/pr.111.004994. Epub 2011 Nov 21.

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