Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction
Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction
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DOI：
10.1016/j.tiv.2017.09.002
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发表时间：
2017-12-01
影响因子：
3.2
通讯作者：
Joy, Melanie S.
中科院分区：
文献类型：
--
作者：
Atilano-Roque, Amandla;Joy, Melanie S.
人有机阴离子转运多肽3A 1（OATP 3A 1）主要在心脏中表达。尽管已知其他OATP介导他汀类药物在肝脏中的摄取，但OATP 3A 1将他汀类药物转运至心肌细胞的能力尚不清楚。在原代人心肌细胞和转染OATP 3A 1基因的HEK 293细胞中分析辛伐他汀酸的多效性效应和摄取。辛伐他汀酸处理减少了硫酸吲哚酚介导的活性氧，并调节了心肌细胞和转染OATP 3A 1基因的HEK 293细胞中OATP 3A 1的表达。我们观察到对OATP 3A 1摄取的pH依赖性效应，在用OATP 3A 1基因转染的HEK 293细胞中，在pH 5.5时辛伐他汀酸摄取更有效。OATP 3A 1摄取辛伐他汀酸的米氏常数（Km）为0.017 +/- 0.002 μ M，Vmax为0.995 +/- 0.027 fmol/min/10（5）个细胞。OATP 3A 1的已知底物（苄青霉素和雌酮-3-硫酸盐）和潜在底物（硫酸吲哚酚和环孢菌素）显著增加辛伐他汀酸的摄取。总之，心肌细胞中OATP 3A 1的存在表明，由于辛伐他汀酸在心肌细胞中富集，该转运蛋白可能调节心脏组织对辛伐他汀酸的暴露。当与OATP底物联合使用时，OATP 3A 1对辛伐他汀酸的摄取增加，表明可能存在影响临床结局的药物相互作用。
Human organic anion transporting polypeptide 3A1 (OATP3A1) is predominately expressed in the heart. The ability of OATP3A1 to transport statins into cardiomyocytes is unknown, although other OATPs are known to mediate the uptake of statin drugs in liver. The pleiotropic effects and uptake of simvastatin acid were analyzed in primary human cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. Treatment with simvastatin acid reduced indoxyl sulfate-mediated reactive oxygen species and modulated OATP3A1 expression in cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. We observed a pH-dependent effect on OATP3A1 uptake, with more efficient simvastatin acid uptake at pH 5.5 in HEK293 cells transfected with the OATP3A1 gene. The Michaelis-Menten constant (K-m) for simvastatin acid uptake by OATP3A1 was 0.017 +/- 0.002 mu M and the V-max was 0.995 +/- 0.027 fmol/min/10(5) cells. Uptake of simvastatin acid was significantly increased by known (benzylpenicillin and estrone-3-sulfate) and potential (indoxyl sulfate and cyclosporine) substrates of OATP3A1. In conclusion, the presence of OATP3A1 in cardiomyocytes suggests that this transporter may modulate the exposure of cardiac tissue to simvastatin acid due to its enrichment in cardiomyocytes. Increases in uptake of simvastatin acid by OATP3A1 when combined with OATP substrates suggest the potential for drug-drug interactions that could influence clinical outcomes.