Increased drug delivery to the brain by P-glycoprotein inhibition

• Published in: Clinical pharmacology and therapeutics Vol. 68; no. 3; pp. 231 - 237
• Main Authors: Sadeque, Abu J. M., Wandel, Christoph, He, Hauibing, Shah, Selina, Wood, Alastair J. J.
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-09-2000
• Subjects: Adrenergic alpha-Antagonists - pharmacology; Adult; Antidiarrheals - blood; Antidiarrheals - metabolism; Antidiarrheals - pharmacokinetics; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Carbon Dioxide - pharmacology; Digestive system; Double-Blind Method; Drug Interactions; Humans; Loperamide - blood; Loperamide - metabolism; Loperamide - pharmacokinetics; Male; Medical sciences; Pharmacology. Drug treatments; Quinidine - pharmacology; Respiration - drug effects; Human; Loperamide; Drug combination; Healthy subject; Toxicity; P Glycoprotein; Central nervous system; Antidiarrheal agent; Opiates; Antiarrhythmic agent; Quinidine; Distribution; Drug interaction; Respiratory depression; Inhibition; Pharmacokinetics; Carrier protein; Brain (vertebrata)
• ISSN: 0009-9236; 1532-6535
• 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.
Clinical Pharmacology & Therapeutics (2000) 68, 231–237; doi: 10.1067/mcp.2000.109156