期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 68, 期 3, 页码 231-237出版社
WILEY
DOI: 10.1067/mcp.2000.109156
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资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL056251] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P01GM031304] Funding Source: NIH RePORTER
- NCRR NIH HHS [RR 00095] Funding Source: Medline
- NHLBI NIH HHS [HL 56251] Funding Source: Medline
- NIGMS NIH HHS [GM 31304] Funding Source: Medline
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.
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