Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?
Frontiers in Pharmacology – January 20, 2021
Source: OpenAlex
Summary
Mescaline, a natural hallucinogen, is significantly transported by the organic cation transporter OCT1, with a maximum transport rate of 642 pmol × mg protein −1 × min −1. Genetic variants of OCT1 show varied transport efficiency; for example, variants *3 and *4 exhibit substantial reductions. In a study assessing 18 psychostimulants, other compounds like methamphetamine and dimethyltryptamine also demonstrated notable transport via OCT2. These findings suggest that genetic differences in transporter activity could lead to significant variations in drug metabolism and potential adverse reactions among individuals.
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 K m 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.