OCT1 mediates hepatic uptake of sumatriptan and loss‐of‐function OCT1 polymorphisms affect sumatriptan pharmacokinetics

Abstract

The low bioavailability of the anti-migraine drug sumatriptan is partially caused by first-pass hepatic metabolism. In this study, we analyzed the impact of the hepatic organic cation transporter OCT1 on sumatriptan cellular uptake, and of OCT1 polymorphisms on sumatriptan pharmacokinetics. OCT1 transported sumatriptan with high capacity and sumatriptan uptake into human hepatocytes was strongly inhibited by the OCT1 inhibitor MPP(+) . Sumatriptan uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg. Plasma concentrations in humans with two deficient OCT1 alleles were 215% of those with fully active OCT1 (P = 0.0003). OCT1 also transported naratriptan, rizatriptan, and zolmitriptan, suggesting a possible impact of OCT1 polymorphisms on the pharmacokinetics of other triptans as well. In conclusion, OCT1 is a high-capacity transporter of sumatriptan and polymorphisms causing OCT1 deficiency have similar effects on sumatriptan pharmacokinetics as those observed in subjects with liver impairment.

Variability and Heritability of Thiamine Pharmacokinetics With Focus on OCT1 Effects on Membrane Transport and Pharmacokinetics in Humans

“…Genotyping for OCT1 was performed on DNA extracted from blood samples via automated solid‐phase extraction (EZ1 DNA Blood Kit; Qiagen, Hilden, Germany). Genotyping was described in detail elsewhere . Briefly, a single‐base primer extension assay was performed to genotype following common genetic variants: Ser14Phe (rs34447885), Arg61Cys (rs12208357), Cys88Arg (rs55918055), Pro117Leu (rs200684404), Ser189Leu (rs34104736), Gly401Ser (rs34130495), Met420del (rs202220802), and Gly465Arg (rs34059508).…”

“…Genotyping was described in detail elsewhere. 36 Briefly, a single-base primer extension assay was performed to genotype following common genetic variants: Ser14Phe (rs34447885), Arg61Cys (rs12208357), Cys88Arg (rs55918055), Pro117Leu (rs200684404), Ser189Leu (rs34104736), Gly401Ser (rs34130495), Met420del (rs202220802), and Gly465Arg (rs34059508). Almost all samples included in the study were genotyped in duplicate, with 100% concordant results.…”

Assay Conditions Influence Affinities of Rat Organic Cation Transporter 1: Analysis of Mutagenesis in the Modeled Outward-Facing Cleft by Measuring Effects of Substrates and Inhibitors on Initial Uptake

“…We also measured the effects of a few mutations on initial rates of tracer flux at 37°C in stably transfected HEK293 cells (Egenberger et al, 2012). In other laboratories, functional analysis of hOCT1 was performed in stably transfected HEK293 cells by measuring tracer flux uptake in confluent cells using incubation times of several minutes duration (Nies et al, 2009;Chen et al, 2010;Tzvetkov et al, 2012;Matthaei et al, 2016).…”

Analysis of membrane transport mechanisms of endogenous substrates using chromatographic techniques

“…Genetically modified animals such as gene‐knockout mice are good models for elucidating the role of transporters in the living body (Jonker, Wagenaar, Van Eijl, & Schinkel, ; Schinkel et al, ). In clinical studies, participants having single‐nucleotide polymorphisms in transporter genes that are associated with loss‐of‐function phenotypes have been analyzed (Matthaei et al, ).…”