Increased drug delivery to the brain by P-glycoprotein inhibition.
BACKGROUND
Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate-dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression.


METHODS
To test this hypothesis, a 16-mg dose of loperamide was administered to eight healthy male volunteers in the presence of either 600 mg quinidine, a known inhibitor of P-glycoprotein, or placebo. Central nervous system 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 alone, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). These changes were not explained by increased plasma loperamide concentrations.


CONCLUSIONS
This study therefore demonstrates first the potential for important 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 reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential.
Sadeque
A J
AJ
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Wandel
C
C
He
H
H
Shah
S
S
Wood
A J
AJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000930:Antidiarrheals / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002245:Carbon Dioxide / Q000494:pharmacology; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D008139:Loperamide / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D011802:Quinidine / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000317:Adrenergic alpha-Antagonists; D000930:Antidiarrheals; D002245:Carbon Dioxide; D008139:Loperamide; D011802:Quinidine