Opioids as Substrates and Inhibitors of the Genetically Highly Variable Organic Cation Transporter OCT1

Author(s)
Marleen J Meyer, Viktoria E Neumann, Hannah Rosa Friesacher, Barbara Zdrazil, Jürgen Brockmöller, Mladen V Tzvetkov
Abstract

Genetic variants in the hepatic uptake transporter OCT1, observed in 9% of Europeans and white Americans, are known to affect pharmacokinetics and efficacy of tramadol, morphine, and codeine. Here, we report further opioids to be substrates and inhibitors of OCT1. Methylnaltrexone, hydromorphone, oxymorphone, and meptazinol were identified as OCT1 substrates. Methylnaltrexone is the strongest OCT1 substrate currently reported. It showed 86-fold higher accumulation in OCT1-overexpressing cells compared to control cells. We observed substantial differences in the inhibitory potency among structurally highly similar morphinan opioids (IC50 ranged from 6.4 μM for dextrorphan to 2 mM for oxycodone). The ether linkage of C4-C5 in the morphinan ring leads to a strong reduction of inhibitory potency. In conclusion, although polyspecific, OCT1 possesses a strong selectivity for its ligands. In contrast to methylnaltrexone and hydromorphone, oxycodone and hydrocodone do not interact with OCT1 and may be safer for use in individuals with genetic OCT1 deficiency.

Organisation(s)
Department of Pharmaceutical Chemistry
External organisation(s)
Ernst Moritz Arndt Universität Greifswald, Georg-August-Universität Göttingen
Journal
Journal of Medicinal Chemistry
Volume
62
Pages
9890-9905
ISSN
0022-2623
DOI
https://doi.org/10.1021/acs.jmedchem.9b01301
Publication date
10-2019
Peer reviewed
Yes
Austrian Fields of Science 2012
Pharmaceutical chemistry
Portal url
https://ucris.univie.ac.at/portal/en/publications/opioids-as-substrates-and-inhibitors-of-the-genetically-highly-variable-organic-cation-transporter-oct1(938401ae-4992-4043-9d68-2ce480744c8e).html