Question - What is the mechanistic basis for the CNS effects associated with loperamide overdose?
Answer - The cited article notes “Loperamide is a known P-glycoprotein (P-gp) substrate. P-gp is a transporter protein primarily active in the intestinal tissue and the blood brain barrier. In normal physiological settings, P-gp can effectively efflux loperamide from the cytosol of the endothelial cells lining the vasculature in the brain to the lumen of the vasculature, effectively preventing access to the brain. However, overdoses of loperamide have shown CNS activity as the P-gp is overwhelmed, allowing intracerebral absorption and thus facilitating euphoric CNS effects.” (Powell JW and Presnell SE. Loperamide as a potential drug of abuse and misuse: Fatal overdoses at the Medical University of South Carolina. 2019 J Forensic Sci. doi: 10.1111/1556-4029.14115)