Tolterodine pharmacokinetics

BrynneN, Svanstrfim C, Aberg-Wistedt A, HallenB, BertlissonL. Fluoxetine inhibits the me-tabolism of tolterodine—pharmacokinetic implications and proposed clinical relevance. BrJ Clin Pharmacol (1999) 48, 553-63. 

Details regarding the pharmacokinetics, contraindica-tions/precautions, and dosing of the five recommended agents (oxybutynin, tolterodine, trospium chloride, solifenacin, and darifenacin) are illustrated in Table 50-3.7 12,14 16 A current clinical controversy is which of these agents should be considered first-line in UUI, and in the case of oxybutynin and... 

Variability in metabolism A subset (approximately 7%) of the population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals ( poor metabolizers ) is by dealkylation via cytochrome P450 3A4 (CYP3A4) to A/-dealkylated tolterodine. The remainder of the population is referred to as extensive metabolizers. Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. 

D6 - Tolterodine is not expected to influence the pharmacokinetics of drugs that are metabolized by cytochrome P450 2D6, such as flecainide, vinblastine, carbamazepine, and tricyclic antidepressants. 

Sathyan G, Dmochowski RR, AppeU RA, Guo C, Gupta SK. Effect of antacid on the pharmacokinetics of extended-release formulations of tolterodine and oxy-butynin. Clin Pharmacokinet 2004 43 1059-68. 

Brynne N, Dalen P, Alvan G, Bertilsson L, Gabrielsson J. The influence of CYP2D6 polymorphism on the pharmacokinetics and dynamics of tolterodine. Clin Pharmacol Ther 1998 63 529-539. 

Tolterodine is eliminated by two different oxidative metabolic pathways hydroxylation, catalysed by CYP2D6, and Z)-alkylation, catalysed by CYP3A. The pharmacokinetics and safety of tolterodine and its metabolites in the absence and presence of ketoconazole have been investigated in healthy volunteers with deficient CYP2D6 activity (poor metabolizers) (55). Clearance of tolterodine fell by 60% during co-administration of ketoconazole, resulting in a 2.1-fold increase in AUC. Thus, caution is needed when ketoconazole and other potent inhibitors of CYP3A are used concomitantly with tolterodine. 

A major consideration in using tolterodine is its pharmacokinetics, specifically its metabolism. The agent is predominantly eliminated by hepatic metabolism, and it exhibits genetic polymorphism. The principal metabolic pathway in extensive metabolizers involves oxidation of the parent drug by the CYP450 isoenzyme 2D6 to the active 5-hydroxymethyl metabolite (DDOl), followed by further oxidation and dealkylation. 

Single-dose interaction studies have demonstrated that concurrent administration of tolterodine LA with antacid leads to a rapid release of drug (70% within 4 hours) and results in a 1.5-fold elevation in tolterodine peak plasma concentration compared with placebo. The clinical implications of this interaction and whether a similar interaction exists with gastric acid suppressants such as the histamine H2 -receptor antagonists and proton pump inhibitors are unclear. In the same study, the pharmacokinetics of oxybutynin XL were unaltered by antacid administration. ... 

In healthy subjects, tolterodine did not aiter the pharmacokinetics or pharmacodynamics of warfarin, but isoiated cases of raised INRs have been reported. 

In a placebo-controlled study in healthy subjects, tolterodine 2 mg twice daily for 7 days did not affect the pharmacokinetics oiR- or 5-warfarin after a single 25-mg dose of warfarin given on day 4, nor were the pharmacokinetics of tolterodine altered by warfarin. In addition, the prothrombin time and factor Vn activity were not altered by tolterodine. ... 

RahirnyM, Hallen B, Narang P. Effect of tolterodine on the anticoagulant actions and pharmacokinetics of single-dose warfarin in healthy volunteers. Arzneimittelforschung (2002) 52, 890-5. 

A randomised, crossover study in 24 women found that tolterodine 2 mg twice daily on days 1 to 14 of two 28-day contraceptive cycles had no effect on the pharmacokinetics of the steroids in a combined oral contraceptive (ethinylestradioFlevonorgestrel 30/150 micrograms). The pharmacokinetics of the tolterodine were also not significantly altered, and the serum levels of estradiol and progesterone indicated that suppression of ovulation continued during both periods of treatment. No special precautions would therefore seem to be needed if these drugs are used concurrently. 

In an identical study in 23 healthy subjects, Maa/ojc increased the maximum plasma level of a single 4-mg dose of extended-release tolterodine (DetrolLA) by 50%, but did not change any other pharmacokinetic parameter (time to maximum level, elimination half-life, AUC). ... 

In a placebo-controlled, crossover study, 14 healthy subjects received du-loxetine 40 mg twice daily and tolterodine 2 mg twice daily for 5 days. Duloxetine increased the steady-state AUC of tolterodine by 71% and its maximum level by 64%. However, duloxetine had no effect on the pharmacokinetics of 5-hydroxymethyl-tolterodine the active metabolite of tolterodine. ... 

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