2. Academic Validation
  3. Opioids as Substrates and Inhibitors of the Genetically Highly Variable Organic Cation Transporter OCT1

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

  • J Med Chem. 2019 Nov 14;62(21):9890-9905. doi: 10.1021/acs.jmedchem.9b01301.
Marleen J Meyer 1 2,  Viktoria E Neumann 2,  Hannah Rosa Friesacher 3,  Barbara Zdrazil 3,  Jürgen Brockmöller 2,  Mladen V Tzvetkov 1 2
Affiliations

Affiliations

  • 1 Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT) , University Medicine Greifswald , 17487 Greifswald , Germany.
  • 2 Institute of Clinical Pharmacology , University Medical Center Göttingen , 37075 Göttingen , Germany.
  • 3 Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry , University of Vienna , 1090 Vienna , Austria.
PMID: 31597043 DOI: 10.1021/acs.jmedchem.9b01301
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.

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