Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity

Aims To investigate the pharmacokinetics and safety of tolterodine and tolt erodine metabolites after single-and multiple-dose administration in the ab sence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3 A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabol isers of debrisoquine. Methods Eight healthy volunteers received single oral doses (2 mg) of tolte rodine L-tartrate. Following a wash-out period of about 3 months, six of th e subjects participated in a multiple-dose (1 mg twice daily) phase of the study. Ketoconazole 200 mg was given once daily for 4-4.5 days during both the single and multiple dose tolterodine administration phases. Blood sampl es were drawn and the pharmacokinetics of tolterodine and its metabolites w ere determined. Results A decrease (P<0.01) inapparent oral clearance of tolterodine, From 10-12 l h(-1) to 4.3-4.7 l h(-1), was obtained during concomitant administr ation of ketoconazole, yielding at least a two-fold increase in the area un der the serum concentration-time curve after single as well as after multip le doses following single dose administration of tolterodine. The mean (+/- s.d.) terminal half-life increased by 50% from 9.7 +/- 2.7 h to 15 +/- 5.4 h in the presence of ketoconazole. Conclusions CYP3A4 is the major enzyme involved in the elimination of tolte rodine in individuals with deficient CYP2D6 activity (poor metabolisers), s ince oral clearance of tolterodine decreased by 60% during ketoconazole coa dministration. This inhibition resulted in 2.1-fold increase in AUC.