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

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; pAz=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 (IDSo 15 and 40 nmol . kg-l, respectively; P<O.Ol). In radioligand binding studies carried out in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic ml-m5 receptors, PNU-200577 was not selective for any muscarinic receptor subtype. Thus, PNU-200577 is similar to tolterodine in terms of antimuscarinic potency, functional selectivity for the urinary bladder in vivo and absence of selectivity for muscarinic receptor subtypes in 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.

A Pharmacoeconomic Model Comparing Two Long-Acting Treatments for Overactive Bladder

“…Our rationale for assigning these varying levels of resources was based on a retrospective study, 29 where patients switching OAB medication during the follow-up period had approximately 12% higher median per-member-per-month (PMPM) total costs from baseline. In comparison, the group that was maintained on the same OAB therapy had approximately 45% lower median PMPM total costs from baseline.…”

Comparative Evaluation of Exocrine Muscarinic Receptor Binding Characteristics and Inhibition of Salivation of Solifenacin in Mice

“…It is known that exocrine glands such as salivary gland contain predominantly the M 3 muscarinic receptor subtype 14,15) and that oxybutynin displays high selectivity for the muscarinic M 3 subtype. 6,7,18) Further, recent data with M 3 subtype knockout mice show that the M 3 subtype is expressed predominantly (70-80%) in the mouse submaxillary gland (Oki et al, unpublished observation). It is therefore possible that the greater binding of oxybutynin to muscarinic receptors in the Homogenates of mouse submaxillary gland were pretreated with oxybutynin (3 mM) and solifenacin (30 mM), and the ten-fold diluted homogenates were used for the measurement of [ 3 H]NMS binding as the no-washout sample.…”

“…Bladder-selective anticholinergic agents such as solifenacin and tolterodine which may reduce or even eliminate these problems are now under development. [6][7][8][9][10][11][12] In particular contrast to oxybutynin, the attenuation of cholinergic responses by solifenacin has been shown to be less potent in salivary gland than in bladder detrusor muscle. However, the mechanism underlying solifenacin's relatively weak inhibition of salivary secretion has not been clarified.…”

“…2,3) Although the efficacy of these agents has been demonstrated, 4,5) their side effects cause problems in geriatric patients. Especially, the dry mouth caused by oral oxybutynin, a more potent inhibitor of cholinergic salivation than bladder contraction, 6,7) often leads to the discontinuation of treatment. Bladder-selective anticholinergic agents such as solifenacin and tolterodine which may reduce or even eliminate these problems are now under development.…”

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Bladder Selectivity Based on In Vivo Drug–Receptor Binding Characteristics of Antimuscarinic Agents for Treatment of Overactive Bladder

“…In addition, tolterodine has been demonstrated to display favorable tissue selectivity for the urinary bladder compared with the salivary glands in cats (40). Tolterodine is extensively metabolized in the liver to form an active metabolite, 5-hydroxymethyl metabolite (5-HM) (41,42). In in vitro experiments, tolterodine and 5-HM competed concentration-dependently with [ 3 H]NMS for binding sites in the bladder, submaxillary gland, and heart of mice; and the potency of both agents was considerably greater than that of oxybutynin (43).…”