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首页> 外文期刊>Clinical Pharmacology and Therapeutics >Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics.
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Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics.

机译：三种转运抑制剂维拉帕米，西咪替丁和丙磺舒对非索非那定药代动力学的不同影响。

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OBJECTIVE: Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics. METHODS: Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing. RESULTS: Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95%CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment. CONCLUSION: This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters.
机译：目的：非索非那定是P-糖蛋白和有机阴离子转运多肽的底物。本研究的目的是比较不同转运抑制剂对非索非那定药代动力学的抑制作用。方法：十二名男性志愿者单次口服口服120 mg的非索非那定。此后，每天服用3次为期6天的疗程，分别是240 mg维拉帕米（P-糖蛋白抑制剂），800 mg西咪替丁（有机阳离子转运蛋白抑制剂）或2000 mg丙磺舒（有机阴离子转运多肽抑制剂）。在第6天以相同剂量的非索非那定以随机方式进行服用。在给药后48小时内监测非索非那定的血浆和尿液浓度。结果：维拉帕米治疗显着提高了血浆峰值浓度2.9倍（95％置信区间[CI]，从2.4到4.0倍），血浆浓度-时间曲线下的面积从时间0到无穷大[AUC（0- fexofenadine的无穷大）]的2.5倍（95％CI，2.0至3.3倍）。西咪替丁治疗期间未发现非索非那定的任何血浆药代动力学参数发生变化。丙磺舒治疗期间AUC（0-无穷大）略有增加，但显着增加了1.5倍（95％CI为1.1至2.4倍）。西咪替丁治疗期间非索非那定的肾脏清除率显着降低至61％（95％CI，50％-98％），丙磺舒治疗期间的肾清除率降至27％（95％CI，20％-58％），但维拉帕米治疗期间未降低。结论：这项研究表明维拉帕米增加了非索非那定的暴露，这可能是由于P-糖蛋白抑制引起的生物利用度的增加，并且由于肾清除率明显降低，丙磺舒略微增加了非索非那定血浆浓度-时间曲线下的面积。但是，可能难以通过对靶标转运蛋白的简单抑制机制来解释这些相互作用。

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