Mu opioid receptor (MOR) agonists comprise the most effective analgesics, but their therapeutic utility is limited by adverse effects. One approach for limiting such effects has been to develop "biased" MOR agonists that show preference for activating G protein over β-Arrestin signaling. However, the notion of biased agonism has been challenged by recent studies. Oliceridine (Olinvyk®, TRV-130, OLC) is a selective MOR agonist approved by the FDA in 2020 for pain management in controlled clinical settings. Oliceridine purportedly demonstrates diminished adverse effects compared to morphine or other MOR agonists, a profile attributed to its biased agonism. However, recent studies suggest that oliceridine does not display biased agonism but instead weak intrinsic efficacy for G protein and β-Arrestin activation. Nevertheless, these insights have been derived from in vitro studies. To better understand oliceridine's in vivo efficacy profile, we performed a comprehensive assessment of its in vitro and in vivo pharmacology using both cultured cells and rodents. In vitro, oliceridine displayed high MOR affinity and weak intrinsic efficacy. In vivo, oliceridine showed impaired brain penetrance and rapid clearance, effects we attributed to its interaction with the P-glycoprotein (P-gp) efflux transporter. Moreover, we found that P-gp was essential for oliceridine's in vivo efficacy and adverse effect profiles. Taken together with prior studies, our results suggest that oliceridine's in vivo efficacy and adverse effect profiles are not attributed solely to its weak intrinsic efficacy or biased agonism but, to a large extent, its interaction with P-gp as well.
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