Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement

Background: The antidiarrheal drug loperamide is frequently used to treat r itonavir-associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its lo w bioavailability and its poor penetration of the blood-brain barrier, both of which might be altered by ritonavir, a potent P-glycoprotein and cytoch rome P4503A inhibitor. Methods. A 16-mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo. Det ailed pharmacokinetics of loperamide and its metabolites were determined ov er 72 hours. Central opioid effects were measured by evaluation of pupil di ameter, cold pressor test, and transcutaneous PCO2 and PO2. Results: Ritonavir caused a major pharmacokinetic interaction, increasing t he area under the concentration-time curve of loperamide from 104 +/- 60 h (.) pmol/ml after placebo to 276 +/- 68 h (.) pmol/ml and delayed formation of the major metabolite desmethylloperamide (time to reach maximum concent ration after drug administration [t(max)], 7.1 +/- 2.6 hours versus 19.6 +/ - 9.1 hours). The urinary metabolic ratio of loperamide increased 3 times w hereas the total molar amount of loperamide and metabolites excreted in uri ne remained unchanged. No central pharmacodynamic effects were observed aft er coadministration. of loperamide with either ritonavir or placebo. Conclusion: This study demonstrates a major metabolic interaction probably by cytochrome P4503A4 with no evidence of P-glycoprotein involvement. This might explain the lack of central effects after ritonavir.