ITRACONAZOLE MODERATELY INCREASES SERUM CONCENTRATIONS OF OXYBUTYNIN BUT DOES NOT AFFECT THOSE OF THE ACTIVE METABOLITE

Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformat ion of oxybutynin is dependent on CYP3A. Because itraconazole, a widel y used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. S erum concentrations of oxybutynin, its active metabolite N-desethyloxy butynin, and itraconazole were monitored over 24 h. Results: Itraconaz ole significantly increased both the area under the serum drug concent ration-time curve (AUC(0-t)) and the peak concentration of oxybutynin twofold. The AUC(0-t) and the peak concentration of N-desethyloxybutyn in were not significantly affected by itraconazole, Itraconazole did n ot change the peak time or the elimination half-life of either oxybuty nin or N-desethyloxybutynin. The occurrence of adverse events after ox ybutynin administration was not increased by itraconazole. Conclusions : Itraconazole moderately increases serum concentrations of oxybutynin , probably by inhibiting the CYP3A-mediated metabolism However, the co ncentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributabl e to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 i nhibiting drugs has only minor clinical significance.