Muscarinic Receptor Binding Characteristics in Rat Tissues after Oral Administration of Oxybutynin and Propiverine.

Oki, Tomomi; Yamada, Shizuo; Tohma, Ayako; Kimura, Ryohei

doi:10.1248/bpb.24.491

Cited by 14 publications

(12 citation statements)

References 21 publications

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“…Thus, the selectivity for the urinary bladder over the brain was relatively low for oxybutynin, suggesting a high feasibility of CNS side effects at pharmacological doses to treat OAB. This finding seems to be in a reasonable agreement with previous observations of oxybutynin shown by pharmacological (Sugiyama et al, 1999) and ex vivo receptor binding (Oki et al, 2001) studies in rats and also by clinical studies (Pietzko et al, 1994;Katz et al, 1998;Todorova et al, 2001;Ancelin et al, 2006). In fact, CNS side effect by oxybutynin occurred in patients with OAB and in older subjects receiving this drug (Scheife and Takeda, 2005;Kay et al, 2006).…”

Section: Discussionsupporting

confidence: 91%

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In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

J Pharmacol Exp Ther

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We evaluated the effects of five clinically used antimuscarinic agents for overactive bladder (OAB) treatment on in vivo muscarinic receptor binding in rat brain by quantitative autoradiography. There was a dose-related decrease in in vivo specific (ϩ)N-[11 C]methyl-3-piperidyl benzilate ([ 11 C](ϩ)3-MPB) binding in each brain region of rats 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. Rank order of the i.v. dose for 50% receptor occupancy (RO 50 ) of antimuscarinic agents in rat brain regions was propiverine Ͼ solifenacin Ͼ tolterodine, oxybutynin. There was a good linear relationship between in vivo (pRO 50 values in the rat hippocampus) and in vitro (pK i values in human M 1 receptors) receptor binding activities of propiverine, solifenacin, and tolterodine. The observed RO 50 value of oxybutynin was approximately five times smaller than the predicted in vitro K i value. The dose ratios of antimuscarinic agents for the brain receptor occupancy (RO 50 ) to the inhibition of carbachol-and volume-induced increases in intravesical pressure (ID 50 ), which reflects in vivo selectivity for the urinary bladder over the brain, were greater for solifenacin, tolterodine, and propiverine than oxybutynin. Darifenacin displayed only a slight decrease in specific [11 C](ϩ)3-MPB binding in the rat brain regions, and it was not dose-related. In conclusion, in vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy may provide fundamental basis for managing central nervous system (CNS) side effects in antimuscarinic therapy for OAB. It is suggested that in the treatment of OAB, CNS side effects can be avoided by antimuscarinic agents with high selectivity for the urinary bladder over the brain.

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Section: Discussionsupporting

confidence: 91%

“…It was shown that only the higher dose (24.8 mol/kg i.v.) of propiverine induced CNS effects in rats and bound to muscarinic receptors in rat brain (Oki et al, 2001). Thus, propiverine may exhibit lower incidence of CNS effects than that of oxybutynin in patients with OAB.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

J Pharmacol Exp Ther

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“…Similar data on these agents were reported in human muscarinic receptor subtypes expressed in Chinese hamster ovary cells (Wuest et al, 2006). Furthermore, oral administration of propiverine at pharmacologically relevant doses (24.8 -248 mol/kg) (Nomura et al, 1989;Oki et al, 2001) produced a significant increase in K d values for [ 3 H]NMS binding in the bladder. The significant increase in K d values was seen 3 h after the oral administration of this drug at the low dose (24.8 mol/kg) and 1 to 12 h at higher doses (74.3, 248 mol/kg).…”

Section: Discussionsupporting

confidence: 73%

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

Yamada

Ito²,

Taki³

et al. 2010

Drug Metab Dispos

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“…Previous studies using radioreceptor assay demonstrated that imidafenacin exerts more selective and longer-lasting distribution in the bladder than in salivary gland and colon in rats (Yamada et al 2011), whereas propiverine and solifenacin distribute in the salivary gland or in other antimuscarinic side effect-related tissue as well as in the bladder (Oki et al 2001(Oki et al , 2005. Yamada et al (2011) reported that imidafenacin excreted in urine may contribute to its selective and long-lasting distribution in the bladder because imidafenacin showed a significant binding to bladder muscarinic receptors in rats following its intravesical instillation at a concentration which corresponds to its urine concentration after oral administration in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats

Yamazaki¹,

Muraki²,

Anraku³

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Imidafenacin (KRP-197) is a novel antimuscarinic agent for overactive bladder treatment. The inhibitory effect of imidafenacin on detrusor contraction has been adopted for assessing their bladder selectivity, but this is becoming less convincing as an effectiveness index. We, therefore, reevaluated the bladder selectivity of imidafenacin and other antimuscarinics using their effects on the bladder capacity as an effectiveness index. Bladder capacity was measured by intermittent cystometry in urethane-anesthetized rats. In the tissues related to antimuscarinic side effects, the inhibitory actions were measured each on salivary secretion by electrical stimulation of chorda tympani, on rhythmical contractions in colon, and on carbamylcholine-induced bradycardia. Imidafenacin, solifenacin succinate, tolterodine tartrate, and propiverine hydrochloride significantly increased the bladder capacity, with minimum effective doses of 0.003, 1, 0.03, and 3 mg/kg (i.v.), respectively. The antimuscarinics tested, except for propiverine hydrochloride, shared a common property of increasing bladder capacity at a dose which did not affect micturition pressure. The relative bladder selectivity of imidafenacin, solifenacin succinate, and tolterodine tartrate was 15-, 1.7-, and 2.5-fold higher over salivary gland; 150-, 1.9-, and 9.2-fold higher over colon; and 50-, 12-, and 4.6-fold higher over heart, respectively, than that of propiverine hydrochloride. Thus, imidafenacin shows the most highly selective for bladder over the tissues related to major antimuscarinic side effects, compared to the other three well-known antimuscarinics tested in the rat.

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Muscarinic Receptor Binding Characteristics in Rat Tissues after Oral Administration of Oxybutynin and Propiverine.

Cited by 14 publications

References 21 publications

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

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

In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats

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