Protein transporters differentially mediate opioid pharmacodynamics as measured by continuous electroenephalogram.

Until recently it was believed that opioid uptake was mediated by passive diffusion; however, we recently demonstrated that brain: plasma partitioning of fentanyl reduced by verapamil, likely by inhibition of inward Oatp‐mediated transport. However, we also demonstrated that brain: plasma partitioning of the opioid loperamide is elevated by verapamil, likely by inhibition of P‐glycoprotein (P‐gp) transport. Hypothesis. Inhibition of transport proteins primarily responsible for transport of specific opioids will variably affect intrinsic activity as measured by a continuously processed electroencephalogram (EEG). Opioid (fentanyl or loperamide) was administered by intravenous infusion to Sprague Dawley rats alone or in combination with the inward and outward transport protein inhibitor verapamil. Amplitudes in the 0.5 to 4.5 Hz frequency band of the EEG were used as pharmacodynamic endpoint. Results were modeled using a sigmoidal E max pharmacodynamic model. Verapamil decreased the intrinsic activity for fentanyl (E max ) by 42% and increased EC 50 by 74%. In contrast, verapamil increased loperamide E max by 142% and decreased EC 50 by 44%. Conclusion. Inhibition of protein tranporters can variably alter the intrinsic activity of opioids. Further, this is the first report of a central effect of loperamide following intravenous infusion. Funding: NIH R01‐ GM47502.09 and the Nema Foundation, Malaysia.