Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans

Background: Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 e nzyme. Reboxetine, a selective norepinephrine reuptake inhibitor, is metabo lized by cytochrome P450 3A4. The potential interaction of reboxetine with this representative from the azole derivative class was examined. Methods: Eleven healthy volunteers received (1) 4 mg reboxetine orally on t he second day of a 5-day regimen of 200 mg ketoconazole once daily and (2) 4 mg reboxetine orally in a crossover design. Plasma concentrations of rebo xetine enantiomers [R,R(-)-reboxetine and the more active S,S(+)-reboxetine ] were measured by high-performance liquid chromatography-tandem mass spect rometry. Effects of ketoconazole on enantiomer pharmacokinetics were assess ed by ANOVA, Results: Ketoconazole increased R,R(-)-reboxetine and S,S(+)-reboxetine mea n area under the plasma concentration-time curves (AUC) by 58% and 43%, res pectively (P < .02), Oral clearance of both enantiomers was consequently de creased 34% and 24%, respectively, by ketoconazole (P < .005). Ketoconazole did not significantly affect maximal plasma concentrations (P > .1). Mean terminal half-life after administration of ketoconazole (21.5 hours and 18. 9 hours) was significantly longer than after reboxetine alone (14.8 hours a nd 14.4 hours; P less than or equal to .005). The AUC ratio for R,R(-)-rebo xetine to S,S(+)-reboxetine was reduced by ketoconazole administration (2.7 6 after ketoconazole versus 2.39; P < .003). Conclusion: Ketoconazole decreases clearance of both reboxetine enantiomers . Although the adverse effect profile for reboxetine was not altered by Ket oconazole, the results of this study suggest that caution should be used an d that a reduction in reboxetine dose should be considered when the two are coadministered.