METABOLISM OF ROPIVACAINE IN HUMANS IS MEDIATED BY CYP1A2 AND TO A MINOR EXTENT BY CYP3A4 - AN INTERACTION STUDY WITH FLUVOXAMINE AND KETOCONAZOLE AS IN-VIVO INHIBITORS

Background: Potential drug-drug interactions can be identified in vitr o by exploring the importance of specific cytochrome P450 (CYP) isozym es for drug metabolism. The metabolism of the local anesthetic ropivac aine to 3-hydroxyropivacaine and (S)-2',6'-pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in v ivo model study we quantitated the role of these 2 isozymes for the me tabolism of ropivacaine. Methods: In a randomized, 3-way crossover stu dy, 12 healthy subjects received a single dose of 40 mg ropivacaine in travenously alone or combined either with 25 mg fluvoxamine as a CYP1A 2 inhibitor or with 100 mg ketoconazole as a CYP3A4 inhibitor twice da ily for 2 days. Venous plasma and urine samples were collected over 10 hours and 24 hours, respectively. The samples were analyzed for ropiv acaine base, 3-hydroxyropivacaine, and (S)-2',6'-pipecoloxylidide. Res ults: Coadministration with fluvoxamine decreased the mean total plasm a clearance of ropivacaine from 354 to 112 mL/min (68%), whereas ketoc onazole decreased plasma clearance to 302 mL/min (15%). The relative c hanges in unbound plasma clearance were similar to the changes in tota l plasma clearance. The ropivacaine half-life (t(1/2)) of 1.9 hours wa s almost doubled during fluvoxamine administration and the plasma conc entration at the end of infusion increased slightly, whereas the corre sponding parameters after ketoconazole administration remained unchang ed. Coadministration with ketoconazole almost abolished the (S)-2',6'- pipecoloxylidide concentrations in plasma, whereas fluvoxamine adminis tration increased the (S)-2',6'-pipecoloxylidide levels. The fraction of dose excreted as 3-hydroxyropivacaine in urine decreased during flu voxamine administration from 39% to 13%. Conclusions: CYP1A2 is the mo st important isozyme for the metabolism of ropivacaine. Drug-drug inte ractions with strong inhibitors of this isozyme could be of clinical r elevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical r elevance.