QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.094508v1 316/3/1137    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Oki, T. Articles by Yamada, S. Search for Related Content PubMed PubMed Citation Articles by Oki, T. Articles by Yamada, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Bladder Diseases Hazardous Substances DB METHYLSCOPOLAMINE NITRATE OXYBUTYNIN

NEUROPHARMACOLOGY

Advantages for Transdermal over Oral Oxybutynin to Treat Overactive Bladder: Muscarinic Receptor Binding, Plasma Drug Concentration, and Salivary Secretion

Department of Pharmacokinetics and Pharmacodynamics and Center of Excellence Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

To clarify pharmacological usefulness of transdermal oxybutynin in the therapy of overactive bladder, we have characterized muscarinic receptor binding in rat tissues with measurement of plasma concentrations of oxybutynin and its metabolite N-desethyl-oxybutynin (DEOB) and salivation after transdermal oxybutynin compared with oral route. At 1 and 3 h after oral administration of oxybutynin, there was a significant increase in apparent dissociation constant (K_d) for specific [N-methyl-³H]scopolamine ([³H]NMS) binding in the rat bladder, submaxillary gland, heart, and colon compared with control values. Concomitantly, submaxillary gland and heart showed a significant decrease in maximal number of binding sites (B_max) for [³H]NMS binding, which lasted until 24 h. Transdermal application of oxybutynin caused dose-dependent increases in K_d values for specific [³H]NMS binding in rat tissues. The increment of K_d values by transdermal oxybutynin was dependent on the application time. Plasma concentrations of oxybutynin and DEOB peaked at 1 h after oral oxybutynin. In contrast, plasma concentrations of oxybutynin increased slowly, depending on the transdermal application time of this drug until 12 h. Suppression of pilocarpine-induced salivation in rats due to transdermal oxybutynin was significantly weaker and more reversible than that by oral oxybutynin, which abolished salivary secretion. The present study has shown that transdermal oxybutynin binds significantly to rat bladder muscarinic receptors without producing both long-lasting occupation of exocrine receptors and cessation of cholinergic salivation evoked by oral oxybutynin. Thus, the present study provides further pharmacological basis for advantage of transdermal over oral oxybutynin in the therapy of overactive bladder.

Address correspondence to: Dr. Shizuo Yamada, Department of Pharmacokinetics and Pharmacodynamics and Center of Excellence Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. E-mail: yamada{at}ys7.u-shizuoka-ken.ac.jp