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 86fold higher accumulation in OCT1-overexpressing cells compared to control cells. We observed substantial differences in the inhibitory potency among structurally highly similar morphinan opioids (IC 50 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.
Three years ago, the sudden onset of the COVID-19 pandemic challenged academia just like any other societal field, while at the same time putting science center stage. Media attention tended to focus on particular disciplines, such as epidemiology and microbiology, and on individual, mostly local, experts. Based on the idea that science as a global, multidisciplinary community has something to offer society beyond the highly specialized output of individual research fields prepared for local, short-term perspectives, the Institute of Technology Assessment of the Austrian Academy of Sciences launched a spontaneous expert survey in June 2021 with a global and interdisciplinary aspiration, addressing three non-standard issues related to the pandemic and its management: side effects, opportunities, and preparedness. In this paper, we present our methodology and the results of our analysis. We conclude with a discussion of potential contributions of technology assessment in times of sudden, global crises.
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