Effect of the CYP2D6*10 genotype on tolterodine pharmacokinetics.

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Oishi M, Chiba K, Malhotra B, Suwa T

Effect of the CYP2D6*10 genotype on tolterodine pharmacokinetics.

Drug Metab Dispos. 2010 Sep;38(9):1456-63. doi: 10.1124/dmd.110.033407. Epub 2010 Jun 7.

PubMed ID

20530222 [ View in PubMed

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Abstract

This study was conducted to investigate the effect of the reduced function allele CYP2D6*10, which can be the cause of an intermediate metabolizer (IM), on tolterodine pharmacokinetics. Tolterodine is mainly metabolized to an active 5-hydroxymethyl metabolite (5-HM) by CYP2D6, and 5-HM is also metabolized by CYP2D6. Asian and white healthy volunteers (n = 108) received once daily multiple doses of tolterodine, and the serum concentrations of tolterodine and 5-HM were measured. All subjects were genotyped for CYP2D6. Tolterodine exposures [area under the curve (AUC)] increased in order of CYP2D6*1/*1 [extensive metabolizer (EM)] < CYP2D6*1/*10 < CYP2D6*10/*10 < CYP2D6*5/*10. It was expected that the order of 5-HM exposure would be reversed. However, the 5-HM AUC increased in the same order as that of tolterodine. This phenomenon was explained by considering CYP2D6 mediation of both production and elimination of 5-HM. The tolterodine and 5-HM exposures in CYP2D6*10/*10 were statistically higher than those for CYP2D6*1/*1 (3- and 1.5-fold, respectively). In CYP2D6*4/*4 [poor metabolizer (PM)], 5-HM was not produced and tolterodine exposure was 20-fold higher than that in CYP2D6*1/*1. With consideration for higher protein binding of tolterodine than 5-HM, the exposure as a sum of the unbound fraction of tolterodine and 5-HM (active moiety) in CYP2D6*10/*10 was 1.8-fold higher than that in CYP2D6*1/*1 and was also higher than that in CYP2D6*4/*4. Simulation using the values of EM and PM demonstrated that the maximum possible active moiety exposure was around the observed values of CYP2D6*5/*10, which were 1.9-fold higher than those for CYP2D6*1/*1. This is the first report to provide an example in which the IM shows higher exposure to pharmacological active moiety than the EM and PM.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Tolterodine	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details