Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

Ole Jensen,Muhammad Rafehi,Lukas Gebauer,Jürgen Brockmöller

doi:10.3389/fphar.2020.609811

Abstract

Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a K m of 24.3 µM and a v max of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants *2 and *7, more strongly reduced in *3 and *4, and lowest in *5 and *6, while *8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with K m values in the range of 7.9–46.0 µM and v max values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the v max 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.

Highlights

Eighteen psychostimulants and hallucinogens were initially screened for their potential to be substrates for different polyspecific organic cation transporter (OCT) and high-affinity monoamine neurotransmitter transporters (Figure 3), as well as for the efflux transporter multidrug and toxin extrusion protein 2 kidney-specific (MATE2-K) (Supplementary Figure S1)
The test compounds were selected based on physicochemical properties that are in accordance with those of typical OCT substrates, OCT1 showed high transport activity at this concentration only for mescaline
In contrast to the substrate-specific but very strong transport activity exhibited by OCT1, moderate (4to 6-fold) cellular uptake by OCT2 was seen for methamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine) and approximately 3-fold for para-methoxymethamphetamine (PMMA) and DMT

Summary

Introduction

Amphetamine and other phenylethylamine derivatives (Figure 1 top) form a large group of such indirect sympathomimetics They are used in the treatment of attention deficit hyperactivity disorder and narcolepsy but are frequently found in illicit drugs (e.g., “speed”, “ecstasy”, “crystal meth”) (Sharma and Couture, 2014; Luethi and Liechti, 2020). Another indirect sympathomimetic is cocaine (Figure 1 bottom left), a tropa-alkaloid and, historically, the first local anesthetic.

Methods

Results

Conclusion