Clinical Oral Doses of Dexamethasone Decreases Intrinsic Clearance of Quinidine, A Cytochrome P450 3A Substrate in Dogs

Abstract

We investigated the effect of dexamethasone (DEX) at clinical doses on the pharmacokinetics of quinidine (QN) in dogs. Dogs (5 healthy 1-year-old male beagles) were orally administered DEX once daily for 5 days at 2.5 or 7.5 mg/day. QN (2 mg/kg) was intravenously injected 3 weeks before and one day after the DEX treatment. The plasma concentration of QN was determined by high-performance liquid chromatography with fluorometric detection. Plasma concentrations of albumin and alpha(1)-acid glycoprotein (AGP) were determined by a bromocresol green method and a single immunodiffusion method, respectively. In order to calculate unbound concentrations of QN in plasma, the binding kinetics of QN in plasma was examined by an ultrafiltration method using pooled plasma from the 5 dogs when they were drug-free. Total body clearance of QN was decreased dose-dependently By the DEX treatment, although the decrease was not statistically significant. Elimination half-lives significantly increased (more than twice at 7.5 mg), and intrinsic clearance significantly decreased (about 50%). The volume of distribution increased significantly (about two-fold). Plasma levels of AGP significantly decreased, and the unbound fraction of QN in plasma significantly increased. Our results demonstrate that clinical doses of DEX significantly affect the pharmacokinetics of QN, a CYP3A substrate in dogs, by decreasing CYP3A activity and plasma AGP levels. There is a possibility that adverse drug-drug interaction occurs during DEX therapy through its effects on CYP3A activity and plasma AGP levels.