Effect of the CYP2D6*10 genotype on tolterodine pharmacokinetics.

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.