Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms
Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms
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DOI：
10.1111/j.1365-2125.2006.02599.x
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发表时间：
2006-04-01
影响因子：
3.4
通讯作者：
Siegmund, W
中科院分区：
文献类型：
--
作者：
Bernsdorf, A;Giessmann, T;Siegmund, W
目的评估辛伐他汀是否影响肠道p -糖蛋白（P-gp）和MRP2的表达，以及这些转运蛋白的底物- β(1)选择性阻滞剂他利洛尔的处置。方法对18例ABCB1、ABCC2、SLCO1B1基因型健康受试者（男10例，女8例，体重指数19.0 ~ 27.0 kg m(-2)）进行慢性辛伐他汀治疗前后静脉注射（30 mg）、单次或重复口服（100 mg / d）他林洛尔的处理情况进行监测。评价辛伐他汀反复口服他林洛尔前后的稳态药代动力学。采用实时逆转录-聚合酶链反应（TaqMan((R))）定量测定辛伐他汀治疗前后十二指肠ABCB1和ABCC2 mRNA的表达。结果辛伐他汀对十二指肠ABCB1和ABCC2的表达无明显影响。辛伐他汀和他利洛尔之间没有明显的药代动力学相互作用。十二指肠ABCB1 mRNA含量与口服他他洛尔的AUC(0-∞)（r = 0.627, P = 0.039）和C-max （r = 0.718, P = 0.013）显著相关。ABCB1和ABCC2基因多态性不影响辛伐他汀和他利洛尔的倾向。SLCO1B1*1b基因携带者与野生型SLCO1B1*1a/*1a基因型携带者相比，后者的半衰期显著缩短（12.2 +/- 1.6 h比14.5 +/- 1.4 h, P = 0.01）。结论辛伐他汀对人体肠道P-gp和MRP2的表达无影响。他林洛尔和辛伐他汀在健康受试者慢性共给药过程中无药代动力学相互作用。
Aims To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-selective blocker talinolol, a substrate of these transporter proteins.Methods The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0-27.0 kg m(-2)) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady-state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real-time reverse transcriptase-polymerase chain reaction (TaqMan((R))).Results Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC(0-infinity) (r = 0.627, P = 0.039) and C-max (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half-life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild-type SLCO1B1*1a/*1a genotype (12.2 +/- 1.6 h vs. 14.5 +/- 1.4 h, P = 0.01).Conclusions Simvastatin does not influence the intestinal expression of P-gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co-administration to healthy subjects.