Molecular Modelling Analysis of the Metabolism of Tolterodine
Tolterodine is a new antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency and urge incontinence. In vitro, TTD has high affinity and specificity for muscarinic receptors and shows selectivity for the urinary bladder over salivary glands in vivo. It is a weak base that is rapidly absorbed in humans and eliminated mainly by metabolism. Two oxidative metabolic pathways of TTD involve hydroxylation and N-dealkylation. Hydroxylation produces 5-HM-TTD and is catalysed by CYP2D6 while the N-dealkylation to produce ND-TTD from tolterodine and ND-5-HM-TTD from 5-HM-TTD is catalysed by CYP3A. Oxidation of 5-HM-TTD produces TTDA. Delakylation of TTDA produces ND-TTDA. The major portion of administered dose is excreted as TTDA and ND-TTDA. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TTD and its primary metabolite M1 have moderately large to large LUMO-HOMO energy differences so that they would be kinetically inert. Thus, although TTD and its metabolites have some electron-deficient regions on their molecular surfaces so that they could react with glutathione and nucleobases in DNA, the rates of such adverse reactions are expected to be low.
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