Maruyama Shuji, Hasuike Naoki, Suzuki Kazuhiro, Yamada Shizuo
Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):463-71. doi: 10.1007/s00210-007-0207-1. Epub 2007 Dec 12.
The present study was undertaken to characterize in vivo muscarinic receptors in peripheral tissues (urinary bladder, submaxillary gland, colon, stomach, heart) of mice, and further to evaluate bladder-selectivity of anticholinergic agents to treat overactive bladder. Following i.v. injection of [3H]QNB in mice, the radioactivity in peripheral tissues was exclusively detected as the unchanged form. The in vivo specific [3H]QNB binding in particulate fraction of tissue homogenates of mice showed a pharmacological specificity which characterized muscarinic receptors. Binding parameters (Kd and Bmax) for in vivo specific [3H]QNB binding differed between mouse tissues. Oral administration of oxybutynin attenuated significantly in vivo specific [3H]QNB binding in all tissues of mice. From ratios of AUCurinary bladder/AUCother tissues of time-dependent muscarinic receptor occupancy, oral oxybutynin has been shown to exert little urinary bladder selectivity. Following oral administration of propiverine, there was a significant reduction of in vivo specific [3H]QNB binding in the urinary bladder, colon and submaxillary gland, but not in the stomach and heart. From the ratios of AUCurinary bladder to AUCsubmaxillary gland or AUCheart, it has been shown that oral propiverine exerts higher selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland and heart. Similarly, tolterodine displayed high selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland. Thus, the present study has demonstrated that [3H]QNB may be a useful ligand for in vivo characterization of muscarinic receptor binding of anticholinergic agents to treat overactive bladder. Propiverine and tolterodine have exhibited in vivo selectivity of muscarinic receptor in the mouse urinary bladder rather than in the submaxillary gland, and such receptor binding specificity may be the reason of lower incidence of dry mouth.
本研究旨在对小鼠外周组织（膀胱、颌下腺、结肠、胃、心脏）中的体内毒蕈碱受体进行表征，并进一步评估抗胆碱能药物治疗膀胱过度活动症的膀胱选择性。给小鼠静脉注射[3H]QNB后，外周组织中的放射性仅以未变化的形式被检测到。小鼠组织匀浆颗粒部分的体内特异性[3H]QNB结合表现出表征毒蕈碱受体的药理学特异性。小鼠组织中体内特异性[3H]QNB结合的结合参数（Kd和Bmax）有所不同。口服奥昔布宁可显著减弱小鼠所有组织中的体内特异性[3H]QNB结合。从时间依赖性毒蕈碱受体占有率的AUC膀胱/AUC其他组织比值来看，口服奥昔布宁几乎没有表现出膀胱选择性。口服丙哌维林后，膀胱、结肠和颌下腺中的体内特异性[3H]QNB结合显著降低，但胃和心脏中未降低。从AUC膀胱与AUC颌下腺或AUC心脏的比值来看，口服丙哌维林对膀胱中毒蕈碱受体的选择性高于颌下腺和心脏。同样，托特罗定对膀胱中毒蕈碱受体的选择性高于颌下腺。因此，本研究表明，[3H]QNB可能是一种用于体内表征抗胆碱能药物治疗膀胱过度活动症时毒蕈碱受体结合的有用配体。丙哌维林和托特罗定在小鼠膀胱中表现出毒蕈碱受体的体内选择性，而非颌下腺，这种受体结合特异性可能是口干发生率较低的原因。
