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.