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

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.