Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity |
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| Authors: | Brynne N Forslund C Hallén B Gustafsson L L Bertilsson L |
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| Affiliation: | Department of Clinical Pharmacology, Pharmacia & Upjohn AB, Stockholm, Sweden. niclas.brynne@eu.pnu.com |
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| Abstract: | AIMS: To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single-and multiple-dose administration in the absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of debrisoquine. METHODS: Eight healthy volunteers received single oral doses (2 mg) of tolterodine l-tartrate. Following a wash-out period of about 3 months, six of the 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 samples were drawn and the pharmacokinetics of tolterodine and its metabolites were determined. RESULTS: A decrease (P<0.01) in apparent oral clearance of tolterodine, from 10- 12 l h-1 to 4.3-4.7 l h-1, was obtained during concomitant administration of ketoconazole, yielding at least a two-fold increase in the area under the serum concentration-time curve after single as well as after multiple 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 tolterodine in individuals with deficient CYP2D6 activity (poor metabolisers), since oral clearance of tolterodine decreased by 60% during ketoconazole coadministration. This inhibition resulted in 2.1-fold increase in AUC. |
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| Keywords: | antimuscarinic CYP2D6 CYP3A4 drug interaction ketoconazole tolterodine urinary incontinence |
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