Combined therapy with atorvastatin and calcineurin inhibitors: No interactions with tacrolimus
Combined therapy with atorvastatin and calcineurin inhibitors: No interactions with tacrolimus
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DOI：
10.1111/j.1600-6143.2005.01005.x
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发表时间：
2005-09-01
影响因子：
8.8
通讯作者：
Maes, BD
中科院分区：
文献类型：
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作者：
Lemahieu, WPD;Hermann, M;Maes, BD
据报道，在同时接受环孢素A （CsA）治疗的患者中，全身暴露于他汀类药物和随之而来的并发症风险增加。这被归因于细胞色素P450 3A4 （CYP3A4）抑制药物分解代谢或p -糖蛋白（PGP）和有机阴离子转运多肽（OATP1B1）的药物转运。目前尚不清楚他汀类药物和他克莫司（Tac）联合使用是否也存在这一缺陷。因此，研究人员对13名健康志愿者进行了阿托伐他汀及其代谢物的药代动力学研究，这些志愿者接受了4天的治疗，同时短暂（12小时）暴露于CsA和Tac。在每次治疗后进行总体CYP、肝脏和肠道CYP3A4 + PGP活性的补充评估，并与基线（无药物）进行比较。当服用CsA时，全身暴露于阿托伐他汀酸及其代谢物显著增加。相比之下，Tac的摄入对阿托伐他汀的药代动力学没有任何影响。同时，CsA可显著降低肝脏和肠道PGP，增加肠道CYP3A4，而阿托伐他汀治疗加或不加Tac均未见效果。基于这些发现，对于需要他汀类药物和钙调磷酸酶抑制剂联合使用的患者，Tac治疗似乎是一种更安全的选择。
Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback.Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4 + PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.