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

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 Km of 24.3 µM and a vmax 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 Km values in the range of 7.9–46.0 µM and vmax 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 vmax 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.

Overlap and Specificity in the Substrate Spectra of Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

“…We also observed that substitutions at the primary nitrogen of the phenylethylamine and tryptamine backbone decreased MAT transport ( Figure 4 and Figure S4 ), this is in line with the historic findings using indirect methods and primary cells [ 26 ]. This also explains the low SERT uptake ratios of the recently shown hallucinogens dimethyl- and diethyltryptamine [ 43 ]. Interestingly and in contrast to the results in MATs, these substitutions at the primary amine improved transport via OCT1 in several cases.…”

“…Recently, we investigated the uptake of different psychostimulants, showing that there is overlap between MATs and OCTs in the uptake of substances which in their chemical structure differ from the typical neurotransmitters. Particularly cathine was transported by both the MATs (DAT and NET), but also by OCT2 [ 43 ]. As opposed to OCT2, OCT1 transported only one of the tested psychostimulants to a significant degree, namely mescaline.…”

“…In addition, as it will be shown in this study, it may well be that OCT2 has the broadest substrate spectrum among the OCTs with respect to small organic cations. With the psychostimulants investigated, no conclusive molecular descriptors differentiating between MAT and OCT substrates could be derived, as these psychostimulants were molecularly too heterogeneous to allow for meaningful pairwise comparisons [ 43 ]. Therefore, we here wanted to derive these predictors by comparative uptake analyses of numerous substances with a phenylethylamine- or tryptamine-based backbone structurally closely related to the monoamine neurotransmitters.…”

Pharmacology of Drugs Used as Stimulants

“…Some stimulants are major substrates of organic cation transporters (OCTs) that mediate liver and kidney uptake for metabolism and excretion. Methamphetamine, amphetamine, (–)‐ephedrine, and particularly cathine, are important substrates of renal OCT2, with cathinone, MDMA, and MDEA of lesser importance 93,94 . Involvement of OCT2 in the renal tubular secretion and excretion of some stimulants may result in individual differences in toxicity and potential for drug‐drug interaction at this transporter 93,94 …”

“…MDMA may act both to increase heat production and reduce heat loss to increase temperature by up around 2°C, and this can lead to severe hyperpyrexia, presumably by a cascade of prohyperthermic events 129 . Patients also present with symptoms ressembling heat stroke, rhabdomyolysis, myoglobinuria, renal failure, liver damage, and disseminated intravascular coagulopathy, and these symptoms may also occur with amphetamine, metamphetamine, and MDEA 70,30–132 . Cutaneous vasoconstriction to reduce heat loss could explain a major component of the temperature actions of MDMA and derivatives, and this may be mediated largely through peripheral actions at α 1 ‐ and α 2 ‐adrenoceptors rather than central serotonergic actions 133–136 .…”