Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT3 antagonists tropisetron and ondansetron
Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT3 antagonists tropisetron and ondansetron
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DOI：
10.1038/tpj.2010.75
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发表时间：
2012-02-01
影响因子：
2.8
通讯作者：
Brockmoeller, J.
中科院分区：
文献类型：
--
作者：
Tzvetkov, M. V.;Saadatmand, A. R.;Brockmoeller, J.
止吐药托烷司琼和昂丹司琼被肝细胞摄取后，会被细胞色素P450 2D 6（CYP 2D 6）代谢失活。我们研究了肝有机阳离子转运蛋白1（OCT 1; SLC 22 A1）是否介导细胞摄取，以及常见的OCT 1功能丧失多态性是否影响两种药物的药代动力学和疗效。托烷司琼和昂丹司琼均抑制过表达OCT 1的HEK 293细胞对ASP的摄取。过表达野生型，但不是OCT 1功能丧失的变体，显着增加托烷司琼的摄取。相应地，具有两个OCT 1功能丧失等位基因的患者托烷司琼血药浓度较高（n=59，P
After uptake into liver cells, the antiemetic drugs tropisetron and ondansetron undergo metabolic inactivation by cytochrome P450 2D6 (CYP2D6). We investigated whether the hepatic organic cation transporter 1 (OCT1; SLC22A1) mediates cellular uptake and whether common OCT1 loss-of-function polymorphisms affect pharmacokinetics and efficacy of both drugs. Both tropisetron and ondansetron inhibited ASP uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations (n=59, P