title: The N-oxide metabolite contributes to bladder selectivity resulting from oral propiverine: muscarinic receptor binding and pharmacokinetics.
abstract: We characterized contribution of N-oxide metabolites [1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide (M-1) and 1-methyl-4-piperidyl benzilate N-oxide (M-2)] to the binding of muscarinic receptors in relation to the pharmacokinetics of propiverine in rats. The in vitro muscarinic receptor binding activity of M-2 was equipotent to that of propiverine, whereas M-1 was much less active. After the oral administration of propiverine (24.8-248 micromol/kg), there was relatively selective and longer-lasting binding of muscarinic receptors in the rat bladder compared with the submaxillary gland as shown by a significant increase in the apparent dissociation constant (K(d)) for specific binding of [N-methyl-(3)H]scopolamine ([(3)H]NMS). In addition, the intravesical instillation of M-2 produced a significant increase in K(d) for specific [(3)H]NMS binding in the rat bladder. Extremely high concentrations of M-1 and M-2 were detected in plasma after the oral administration of propiverine. The concentration of unbound M-2 was much higher than that of M-1 and propiverine in the rat plasma. The sum of maximal plasma unbound propiverine equivalents (C(max)) after the oral administration of propiverine at doses of 24.8, 74.3, and 248 micromol/kg was 66.0, 303, and 509 nM, respectively. The sum of corresponding area under the time-concentration curve from 0 to 12 h was 194, 2123, and 4645 nM . h, respectively. In fact, the unbound concentration of M-2 comprised more than 90% of sum of unbound propiverine equivalents in the plasma. After oral treatment with propiverine, the bladder showed the highest concentration of M-2, indicating specific distribution of this metabolite into the target organ. Thus, M-2 may contribute greatly to the relatively selective and long-lasting occupation of bladder muscarinic receptors after oral administration of propiverine.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan. yamada@u-shizuoka-ken.ac.jp
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Yuko
authors.initials: Y
authors.lastname: Taki
authors.forename: Masanao
authors.initials: M
authors.lastname: Seki
authors.forename: Masato
authors.initials: M
authors.lastname: Nanri
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yamashita
authors.forename: Kayo
authors.initials: K
authors.lastname: Morishita
authors.forename: Ikumi
authors.initials: I
authors.lastname: Komoto
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001561:Benzilates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D018680:Cholinergic Antagonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism*
chemical_list: D001561:Benzilates; D018680:Cholinergic Antagonists; D011976:Receptors, Muscarinic; C015586:propiverine