Metabolism of ropinirole is mediated by several canine CYP enzymes

Abstract

Background: Ropinirole has been shown to provoke vomiting in dogs by activating the dopamine D2-like receptors in the chemoreceptor trigger zone. In humans, ropinirole is metabolized primarily by CYP1A2. Corresponding dog CYP1A2 is known to be a polymorphic enzyme which can cause variation in pharmacokinetics of compounds metabolised via this enzyme. Objectives:The aim of this study was to understand metabolic clearance of ropinirole in dogs, the enzymes involved in ropinirole metabolism and specially to estimate whether the clearance can be sensitive towards the polymorphism of canine CYP1A2.Methods: Metabolism of ropinirole was studied in dog hepatocytes and specific recombinant canine CYP isoforms. Metabolite identification and metabolite formation were evaluated using LC-mass spectrometry.Results: Ropinirole was moderately stable in dog hepatocytes with Cl int of 16.3 μL/min/million cells, and the metabolites detected were 7-hydroxy ropinirole and respective glucuronide conjugate as well as despropyl ropinirole. Regarding recombinant CYPs either 7-hydroxy ropinirole, despropyl ropinirole or both were detected for each CYP isoform studied. The highest rates of metabolite formation were observed in CYP2B11, CYP2C21, CYP2D15, CYP1A2 and CYP1A1. Fluvoxamine, a fairly selective human CYP1A/CYP2C19 inhibitor inhibited ropinirole metabolism by CYP1A1, CYP1A2, CYP2B11, CYP2C21 and CYP2D15 for 65.8%-100% showing no selectivity towards canine CYP isoforms. Conclusions:Although human metabolism of ropinirole is mainly mediated through CYP1A2, the current study shows that several canine CYP isoforms are able to contribute to the clearance of ropinirole in dogs. This is expected to reduce a possible impact of canine CYP1A2 polymorphism on ropinirole pharmacokinetics.