OIV-B-1Dynamic interplay between hepatic drug transport and metabolism - the erythromycin breath test

Abstract

BACKGROUND The erythromycin breath test (ERBT) has been widely used as a phenotypic measure of CYP3A activity in individuals and its modulation by inhibitors or inducers. However, it is not entirely clear what this trait measure actually reflects since, in addition to CYP3A, animal studies suggest that P-glycoprotein is also involved in erythromycin's hepatic disposition. Thus, studies were undertaken to determine the effect of tariquidar, a potent P-glycoprotein inhibitor that does not affect CYP3A activity, on the ERBT and on the CYP3A-mediated metabolism of midazolam - a non P-glycoprotein substrate. METHODS A randomized, double-blind, 2-way crossover trial was performed in 8 healthy subjects involving the intravenous administration of either placebo or tariquidar (150 mg over 30 min) on 2 study days separated by at least 2 weeks. On both days, a 1-hr ERBT was performed followed by determination of midazolam's systemic clearance after a 1 mg intravenous dose. RESULTS Tariquidar increased the ERBT value in all subjects by a median of 2.3-fold (range 1.4 to 3.2-fold; p = 0.012). By contrast, midazolam's systemic clearance after tariquidar was unchanged (p=0.25). CONCLUSION Hepatic P–glycoprotein is an important determinant of the ERBT and a potentially confounding factor in interpreting the meaning of the trait measure. Additionally, the results demonstrate the dynamic interplay between hepatic drug transport and metabolism of dual CYP3A/P-glycoprotein substrates. Clinical Pharmacology & Therapeutics (2005) 79, P33–P33; doi: 10.1016/j.clpt.2005.12.118