Increased drug delivery to the brain by P-glycoprotein inhibition

Clin Pharmacol Ther. 2000 Sep;68(3):231-7. doi: 10.1067/mcp.2000.109156.


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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Adrenergic alpha-Antagonists / pharmacology*
  • Adult
  • Antidiarrheals / blood
  • Antidiarrheals / metabolism*
  • Antidiarrheals / pharmacokinetics
  • Brain / drug effects*
  • Brain / metabolism
  • Carbon Dioxide / pharmacology
  • Double-Blind Method
  • Drug Interactions
  • Humans
  • Loperamide / blood
  • Loperamide / metabolism*
  • Loperamide / pharmacokinetics
  • Male
  • Quinidine / pharmacology*
  • Respiration / drug effects*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Adrenergic alpha-Antagonists
  • Antidiarrheals
  • Carbon Dioxide
  • Loperamide
  • Quinidine