Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects
Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects
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昂丹司琼对健康受试者二甲双胍药代动力学和反应的影响
DOI：
10.1124/dmd.115.067223
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发表时间：
2016-04-01
影响因子：
3.9
通讯作者：
Shu, Yan
中科院分区：
文献类型：
--
作者：
Li, Qing;Yang, Hong;Shu, Yan
5 - 羟色胺 - 3（5 - HT3）受体拮抗剂如昂丹司琼已用于预防和治疗恶心和呕吐超过20年。本研究旨在确定昂丹司琼是否可作为一种引发药物，在人体内导致转运体介导的药物 - 药物相互作用。12名无亲缘关系的中国男性健康志愿者被纳入一项前瞻性、随机、双盲、交叉研究，以研究昂丹司琼或安慰剂对二甲双胍药代动力学的影响以及机体对二甲双胍的反应，二甲双胍是有机阳离子转运体以及多药和毒素外排转运体（MATEs）的一种特征明确的底物。与安慰剂相比，昂丹司琼治疗使二甲双胍的Cmax在统计学上显著升高（18.3 ± 5.05对15.2 ± 3.23；P = 0.006），并且使二甲双胍的肾清除率明显降低37%（与安慰剂相比，P = 0.001）。有趣的是，昂丹司琼治疗还在统计学上显著改善了受试者的葡萄糖耐量，这表现为口服葡萄糖耐量试验中葡萄糖曲线下面积更小（10.4 ± 1.43），而安慰剂组为（11.5 ± 2.29 mmol·mg/L）（P = 0.020）。昂丹司琼本身可能影响人体受试者的葡萄糖内稳态，但我们的临床研究，结合我们之前在细胞和动物模型中的发现，表明昂丹司琼可通过其对人体内MATE转运体的强效抑制作用导致药物 - 药物相互作用。
The 5-hydroxytryptamine-3 (5-HT3) receptor antagonists such as ondansetron have been used to prevent and treat nausea and vomiting for over 2 decades. This study was to determine whether ondansetron could serve as a perpetrator drug causing transporter-mediated drug-drug interactions in humans. Twelve unrelated male healthy Chinese volunteers were enrolled into a prospective, randomized, double-blind, crossover study to investigate the effects of ondansetron or placebo on the pharmacokinetics of and the response to metformin, a well-characterized substrate of organic cation transporters and multidrug and toxin extrusions (MATEs). Ondansetron treatment caused a statistically significantly higher Cmax of metformin compared with placebo (18.3 ± 5.05 versus 15.2 ± 3.23; P = 0.006) and apparently decreased the renal clearance of metformin by 37% as compared with placebo (P = 0.001). Interestingly, ondansetron treatment also statistically significantly improved glucose tolerance in subjects, as indicated by the smaller glucose area under the curve in the oral glucose tolerance test (10.4 ± 1.43) as compared with placebo (11.5 ± 2.29 mmol∙mg/l) (P = 0.020). It remains possible that ondansetron itself may affect glucose homeostasis in human subjects, but our clinical study, coupled with our previous findings in cells and in animal models, indicates that ondansetron can cause a drug-drug interaction via its potent inhibition of MATE transporters in humans.