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Ketoconazole Inhibits the Metabolism of Tolterodine in Subjects With Deficient CYP2D6 Activity

Ketoconazole Inhibits the Metabolism of Tolterodine in Subjects With Deficient CYP2D6 Activity

N Brynne, C Forslund, B Hallén, L L Gustafsson, L Bertilsson

Br J Clin Pharmacol. 1999 Oct;48(4):564-72.

PMID: 10583027

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
ALP124937515	Tolterodine L-tartrate		124937-51-5 (free base)	Price

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