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 biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely 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. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h.


RESULTS
Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0-t) and the peak concentration of oxybutynin twofold. The AUC0-t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole.


CONCLUSIONS
Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.
Lukkari
E
E
Department of Clinical Pharmacology, University of Helsinki, Finland.
Juhakoski
A
A
Aranko
K
K
Neuvonen
P J
PJ
D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D008333:Mandelic Acids / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics
D000935:Antifungal Agents; D018680:Cholinergic Antagonists; D008333:Mandelic Acids; D017964:Itraconazole; C032681:desethyloxybutynin; C005419:oxybutynin