Consequences of CYP2D6 polymorphism for the disposition and dynamics of tolterodine : a novel drug in the treatment of urinary bladder overactivity

Sammanfattning: The pharmacokinetics and pharmacological effects of tolterodine were studied in man following administration of increasing oral and intravenous single-doses. The influence of metabolic phenotype in extensive and poor metabolizers of debrisoquine was determined. The effect of tolterodine on the major drug metabolizing cytochrome P450 (CYP) isozymes 1A2, 2C19, 2D6 and 3A4 was studied in vivo by measurements of metabolic ratios of probe drugs. Changes in tolterodine disposition during potent CYP2D6 inhibition in psychiatric patients were evaluated, and during potent CYP3A4 inhibition among healthy poor metabolizers of debrisoquine. Tolterodine was rapidly absorbed but showed a pronounced variation in the absolute bioavailability among individuals following oral administration, which indicated high first-pass elimination. The terminal half- life was 2-3 h when it was first administered to man. Two different metabolic pathways were identified, hydroxylation and N-dealkylation resulting in predominantly tolterodine acid and N-dealkylated tolterodine, respectively, in urine. Effects on heart-rate, accommodation and salivation of tolterodine suggested no muscarinic subreceptor selectivity, rather an additive effect of an active metabolite. The prolonged half-life in some individuals associated with high metabolic ratios of debrisoquine showed a relation to the polymorphic hepatic isozyme, CYP2D6. It was determined that most of the biotransformation of the in vitro equipotent 5-hydroxy metabolite, 5-HM, was catalysed by CYP2D6 in extensive metabolizers of debrisoquine. The poor metabolizers showed no quantifiable serum concentrations of 5-HM; instead they had higher levels of the parent compound. The minor differences in effects on heart rate and salivation between the two phenotypes were explained by in vitro equipotency of tolterodine and 5-HM, and the tenfold higher unbound fraction of the metabolite in serum. It was concluded that in extensive metabolizers the main active principle was 5-HM and in poor metabolizers tolterodine, and the same dose may be used in both phenotypes. Other metabolites apparently do not seem to contribute to the pharmacological effect of tolterodine. In healthy subjects tolterodine did not affect the metabolic probe drugs caffeine (CYP1A2), debrisoquine (CYP2D6) and omeprazole (CYP2C19 and CYP3A4). Therefore, it was considered unlikely that tolterodine inhibits the metabolism of drugs that are substrates of these CYP isozymes. The serum concentrations of both tolterodine and 5-HM were generally higher in subjects with I functional CYP2D6 gene compared to subjects with 2 genes. In extensive metabolizer patients the potent inhibition of CYP2D6 by fluoxetine did not change the effective exposure after tolterodine administration. Therefore, dose adjustment of tolterodine during fluoxetine cotreatment is not required. Coadministration of the potent CYP3A4 inhibitor ketoconazole and tolterodine in a panel of poor metabolizers, increased effective exposure. Therefore, only half the recommended dose of tolterodine should be used when given with potent CYP3A4 inhibitors. It was also demonstrated that CYP3A4 catalyses the major route of elimination, N-dealkylation, in poor metabolizers.