title: 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 vitro, 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 (ID50 15 and 40 nmol.kg-1, respectively; P < 0.01). In radioligand binding studies carried out in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic m1-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 antimuscarinic potency, similar serum concentration and lower degree of protein binding.
authors.affiliation: Medical Department Urology, Pharmacia & Upjohn AB, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Nilvebrant
authors.forename: P G
authors.initials: PG
authors.lastname: Gillberg
authors.forename: B
authors.initials: B
authors.lastname: Sparf
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects; D002217:Carbachol; D002415:Cats; D003408:Cresols / Q000378:metabolism* / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010665:Phenylpropanolamine; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
chemical_list: C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D002217:Carbachol; D000109:Acetylcholine