Increased drug delivery to the brain by P-glycoprotein inhibition

Background: Although the antidiarrheal loperamide is a potent opiate, it do es not produce opioid central nervous system effects at usual doses in pati ents. On the basis of in vitro studies demonstrating that loperamide is a s ubstrate for the adenosine triphosphate-dependent efflux membrane transport er P-glycoprotein, we postulated that inhibition of P-glycoprotein with qui nidine would increase entry of loperamide into the central nervous system w ith resultant respiratory depression. Methods: To test this hypothesis, a 16-mg dose of loperamide was administer ed to eight healthy male volunteers in the presence of either 600 mg quinid ine, a known inhibitor of P-glycoprotein, or placebo. Central nervous syste m effects were measured by evaluation of the respiratory response to carbon dioxide rebreathing as a measure of opiate-induced respiratory depression. Results: Loperamide produced no respiratory depression when administered al one, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). These changes were not expla ined by increased plasma loperamide concentrations. Conclusion: This study therefore demonstrates first the potential for impor tant drug interactions to occur by a new mechanism, namely, inhibition of P -glycoprotein, and second that the lack of respiratory depression produced by loperamide, which allows it to be safely used therapeutically, can be re versed by a drug causing P-glycoprotein inhibition, resulting in serious to xic and abuse potential.