Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance.
OBJECTIVE
Loperamide is a peripherally acting mu opioid receptor agonist and an avid substrate for P-glycoprotein. This may give rise to drug-drug interactions and increased risk for central adverse effects. The objective of this study was to re-evaluate the predictability of non-clinical data using loperamide as a probe P-glycoprotein substrate. We searched the literature for papers containing data on drug-drug interactions of loperamide-containing products in humans. We also reviewed the internal worldwide safety database of Johnson & Johnson for spontaneous case reports suggestive of a central opioid effect after coadministration of loperamide with a P-glycoprotein inhibitor or substrate.


RESULTS
Only one of the ten studies in our review supported the finding that inhibition of P-glycoprotein is associated with clinically relevant signs or symptoms of central nervous system (CNS) depression/opioid toxicity of loperamide. None of the 25 spontaneous case reports of interest were suggestive of signs or symptoms of CNS depression/opioid toxicity due to coadministration of loperamide and a P-glycoprotein inhibitor or substrate.


CONCLUSIONS
Based on a review of the literature and a cumulative review of the spontaneous case reports, there is insufficient evidence that an interaction between loperamide and a P-glycoprotein inhibitor or substrate is associated with clinical symptoms of CNS depression/opioid toxicity when loperamide is taken at the recommended dose.
Vandenbossche
Joris
J
Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium. jvdbossc@its.jnj.com
Huisman
Maarten
M
Xu
Yimei
Y
Sanderson-Bongiovanni
Dawn
D
Soons
Paul
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000701:Analgesics, Opioid / Q000009:adverse effects*; D002490:Central Nervous System / Q000187:drug effects*; D004347:Drug Interactions; D006801:Humans; D008139:Loperamide / Q000009:adverse effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D008139:Loperamide