TheN-Oxide Metabolite Contributes to Bladder Selectivity Resulting from Oral Propiverine: Muscarinic Receptor Binding and Pharmacokinetics

Abstract

ABSTRACT:We

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

“…Moreover, peroxisomal catalase also accumulated in the cytosol and nuclei of propiverine-treated rats concurrently with DAAO. Taken together, our study indicates that Propiverine-N-oxide was also found to be the major metabolite formed in rats when administered orally, thus suggesting a similar pharmacological handling in humans and rats (Yamada et al 2010). In order to attain drug approval for propiverine in Japan and later in the EU, preclinical testing was carried out in mice, rats and dogs (Inoue et al 1989;Kohda et al 1989;Nakano et al 1989;Yamashita et al 1989Yamashita et al , 1990.…”

Up-regulation of nicotinic and muscarinic receptor mRNA in rat bladder by repeated administration of nicotine in relation to the pharmacokinetics

“…Further, the urine concentration of nicotine was about 4-fold higher than the plasma concentration (Onoue et al, in press). Recently, we revealed that urothelial muscarinic receptors were significantly affected by antimuscarinic agents excreted in the urine directly from the bladder luminal side as well as the circulating bloods (Yamada et al, 2010(Yamada et al, , 2011. Thus, the high concentration of nicotine excreted into urine likely contributed to the selective increase in bladder muscarinic receptors.…”

The muscarinic receptor antagonist propiverine exhibits α1-adrenoceptor antagonism in human prostate and porcine trigonum

“…They should also take into account that propiverine and its various metabolites differ in their in vivo plasma concentrations [23]. For each of them, the relative contribution of the three molecular targets may differ in the generation of bladder selectivity and the overall relaxing effect in the lower urinary tract [24]. Even if propiverine itself turns out to have too little α 1 -antagonism in vivo, it is an exciting starting point for the future synthesis of balanced α 1 /muscarinic receptor antagonists.…”