CYP3A inhibition increases plasma levels of vernarinone in humans

In vitro studies have shown that CYP3A contributes to the metabolism of vesnarinone, a quinolinone undergoing clinical evaluation for the treatment of chronic congestive heart failure. To define the role of CYP3A on vesnarinone's metabolism in vivo we administered the CYP3A inhibitor erythromycin to 12 healthy volunteers. CYP3A activity was assessed by the erythromycin breath test (ERBT) performed prior to and after 7 d of erythromycin 500 mg t.i.d.. Following the ERBT vesnarinone 60 mg p.o. was administered. Erythromycin pretreatment increased both plasma AUCtot from 167.6±29.9(mean±SD) to 276.4±83.9mcg/mLxhr (P<0.001, Figure) and Cmax from 2.8±0.4 to 3.1 ±0.4 mcg/mL (P<0.05). Systemic clearance was reduced from 368.8±67.1 to 234.6±64.3 ml/hr (P<0.001). Reduction in CYP3A activity by erythromycin was confirmed by a 35±20% decrease in ERBT (P<0.001). Thus, the coadministration of vesnarinone with the CYP3A inhibitor, erythromycin, reduces the elimination of vesnarinone and implies that CYP3A contributes significantly to vesnarinone clearance in vivo and may account for interindividual variability in plasma concentrations and differential effects on mortality noted in clinical trials with vesnarinone.