Relationships between Inhibition, Transport and Enhanced Transport via the Organic Cation Transporter 1.

Ole Jensen,Jürgen Brockmöller,Lukas Gebauer,Christof Dücker

doi:10.3390/ijms23042007

Ole Jensen, Jürgen Brockmöller + Show 2 more

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https://doi.org/10.3390/ijms23042007

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Abstract

The organic cation transporter 1 (OCT1, SLC22A1) transports a large number of structurally diverse endogenous and exogenous substrates. There are numerous known competitive and non-competitive inhibitors of OCT1, but there are no studies systematically analyzing the relationship between transport, stimulation, and inhibition. Here, we tested in vitro OCT1 inhibition by OCT1 substrates and transport of OCT1 inhibitors under uniform analytical conditions. Beyond inhibition testing with two model substrates, we tested nine additional OCT1 substrates for their mutual inhibition. Inhibition of ASP+ uptake by most OCT1 substrates was weak. The model substrate sumatriptan, with its moderately stronger inhibitability, was used to confirm this. Interestingly, OCT1 substrates exhibiting stronger OCT1 inhibition were mainly biaromatic β-agonistic drugs, such as dobutamine, fenoterol, ractopamine and ritodrine. Biaromatic organic cations were both, strong inhibitors and good substrates, but many OCT1 substrates showed little pairwise inhibition. Surprisingly, sumatriptan did significantly enhance dobutamine uptake. This effect was concentration dependent and additional experiments indicated that efflux inhibition may be one of the underlying mechanisms. Our data suggests, that OCT1 substrates are mainly weak OCT1 inhibitors and among those inhibiting well, noncompetitive inhibition could be responsible. Weak competitive inhibition confirms that OCT1 inhibition screenings poorly predict OCT1 substrates. Additionally, we showed that the OCT1 substrate sumatriptan can enhance uptake of some other OCT1 substrates. OCT1 transport stimulation was already observed earlier but is still poorly understood. Low OCT1 uptake inhibition and strong OCT1 efflux inhibition could be mechanisms exploitable for enhancing transport.

Highlights

IntroductionMany endogenous and exogenous substances, among them many drugs, are either inhibitors or substrates of OCT1, or both [3,4,5,6,7,8,9,10,11]
We present a large database on inhibition and transport by OCT1, and subsequent experiments explaining their relationship (Figure 1)
We found that some OCT1 substrates, such as naratriptan, sulpiride and sumatriptan, showed little to no inhibition of the transport of 9 of the 10 tested substrates

Summary

Introduction

Many endogenous and exogenous substances, among them many drugs, are either inhibitors or substrates of OCT1, or both [3,4,5,6,7,8,9,10,11]. OCT1 is genetically highly polymorphic and frequent variants have reduced transport activity or complete loss of function. With some drug–substrates of OCT1, deficient or very low activity of this transporter may have contributed to the access mortality of the respective drug [12]. Substances that inhibit OCT1 could mimic genetic deficiency (so-called phenocopies). The physiological role of most OCTs remains uncertain, at least, complete loss of OCT1 activity is not associated with major pathologies. Loss of OCT activity may be compensated by other polyspecific transporters

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