Tolterodine – a new bladder-selective antimuscarinic agent

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

“…(R/S)-OXY and (R/S)-N-desethyloxybutynin ((R/S)-DEOB), a pharmacologically active metabolite of (R/S)-OXY, inhibit muscarinic acetylcholine receptors in the bladder, especially antagonizing M 2 and M 3 receptors, which mainly mediate direct contractile response in the bladder 3) and the affinities of both compounds for M 3 receptors are higher than those for M 2 receptors. 4,5) Both (R/S)-OXY and (R/S)-DEOB have an asymmetric carbon, and the (R)-enantiomers ((R)-OXY and (R)-DEOB, respectively) have an antimuscarinic effect on the bladder smooth muscle greater than their corresponding (S)-enantiomers ((S)-OXY and (S)-DEOB, respectively).6,7) Although several reports have evaluated the relationships between PK exposure and antimuscarinic effects after the administration of (R/S)-OXY, 3,[8][9][10][11][12][13] most of them were not focused on the binding to muscarinic receptors, the competition of (R/S)-DEOB with (R/S)-OXY for the muscarinic receptor binding sites or the difference of potency between (R)-and (S)-enantiomers. In addition, there are few reports elucidating the receptor occupancy to show suitable pharmacological effects of (R)-OXY and (R)-DEOB.…”

“…(R/S)-OXY and (R/S)-N-desethyloxybutynin ((R/S)-DEOB), a pharmacologically active metabolite of (R/S)-OXY, inhibit muscarinic acetylcholine receptors in the bladder, especially antagonizing M 2 and M 3 receptors, which mainly mediate direct contractile response in the bladder 3) and the affinities of both compounds for M 3 receptors are higher than those for M 2 receptors. 4,5) Both (R/S)-OXY and (R/S)-DEOB have an asymmetric carbon, and the (R)-enantiomers ((R)-OXY and (R)-DEOB, respectively) have an antimuscarinic effect on the bladder smooth muscle greater than their corresponding (S)-enantiomers ((S)-OXY and (S)-DEOB, respectively).…”

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

“…In an attempt to reduce serious side-effects, such as dry mouth, a number of compounds have been synthesized and evaluated in terms of pharmacological specificity in the bladder relative to the parotid gland. 4,5) Also, a new drug delivery system for oxybutynin has been used clinically and found to be an effective dosage form. 6) Although there are many studies dealing with the pharmacological effects and in vitro receptor binding affinities of anticholinergic agents, 3,[7][8][9] very little in vivo data are available regarding the muscarinic receptor binding characteristics (extent and time-course) in tissues following systemic administration of anticholinergic agents.…”

Comparative Evaluation of Exocrine Muscarinic Receptor Binding Characteristics and Inhibition of Salivation of Solifenacin in Mice

“…2,3) Although the efficacy of these agents has been demonstrated, 4,5) their side effects cause problems in geriatric patients. Especially, the dry mouth caused by oral oxybutynin, a more potent inhibitor of cholinergic salivation than bladder contraction, 6,7) often leads to the discontinuation of treatment. Bladder-selective anticholinergic agents such as solifenacin and tolterodine which may reduce or even eliminate these problems are now under development.…”

“…Bladder-selective anticholinergic agents such as solifenacin and tolterodine which may reduce or even eliminate these problems are now under development. [6][7][8][9][10][11][12] In particular contrast to oxybutynin, the attenuation of cholinergic responses by solifenacin has been shown to be less potent in salivary gland than in bladder detrusor muscle. However, the mechanism underlying solifenacin's relatively weak inhibition of salivary secretion has not been clarified.…”