Antimuscarinic Potency and Bladder Selectivity of PNU‐200577, a Major Metabolite of Tolterodine

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Abstract
PNU‐200577 (labcode DD 01 [(R)‐N,N‐diisopropyl‐3‐(2‐hydroxy‐5‐hydroxymethylphenyl)‐3‐phenylpropanamine) is a major pharmacologically active metabolite of tolterodine, a new muscarinic receptor antagonist intended for the treatment of an overactive bladder.In virro, PNU‐200577 produced a competitive and concentration‐dependent inhibition of carbachol‐induced contraction of guinea‐pig isolated urinary bladder strips (KB=0.84 nM; pA2=9. 14).In vivo, PNU‐200577 was significantly more potent at inhibiting acetylcholine‐induced urinary bladder contraction than electrically induced salivation in the anaesthetised cat (ID5015 and 40 nmol. kg−l, respectively; Pin vivoand absence of selectivity for muscarinic receptor subtypesin vitro. The results of this study clearly indicate that PNU‐200577 contributes to the therapeutic action of tolterodine, in view of its high antimuscarinlc potency, similar serum concentration and lower degree of protein binding.