Development of therapeutic agents for urinary incontinence by in vivo analysis of dru-receptor binding characteritics

通过体内分析 dru-受体结合特性开发尿失禁治疗剂

• 批准号: 11672271
• 负责人: YAMADA Shizuo
• 金额: $ 1.98万
• 依托单位: University of Shizuoka
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672271/
• 关键词: Urinary incontinence; Propiverine; Oxybutynin; Transdermal therapeutic sys em; Muscarinic receptors; Urinary bladder; submaxillary gland; Receptor binding; プロピベリン

Anticholinergic agents such as propiverine and oxybutynin (Oxy) are widely used for the treatment of micturition and urge urinary incontinence. However, the use of these drugs is often limited by systemic side effects such as dry mouth known to occur frequently when they were orally administered, and also by short-duration of action. To develop effective agents in the therapy of DI, we characterized muscarinic receptor binding in rat tissues after the oral administration of propiverine and oxybutynin and after the transdermal application of Oxy (MM-801).[Experiment I] : Oral administration of oxybutynin caused a significant increase in the apparent dissociation constant (K_d) for specific (-)-[^3H]QNB binding in the rat bladder, prostate, submaxillary gland, heart and cerebral cortex, compared with each of the control values. Also, in the submaxillary gland of these rats, there was a reduction in the maximal number of binding sites (B_<max>) for (-)-[^3H]QNB binding. Similarly, oral ad … More ministration of propiverine brought about a significant increase in the K_d values for (-)-[^3H] QNB binding in rat tissues including the bladder, and greater increase in K_d values was seen in the rat prostate, heart and submaxillary gland. On the other hand, oral administration of propiverine, unlike oxybutynin, resulted in very little reduction in the B_<max> valules for (-)-[^3H] QNB binding in the submaxillary gland. In conclusion, the present study has shown that oxybutynin and propiverine, after oral administration, bind significantly to muscarinic receptors in tissues such as the bladder and that oxybutynin appears to exhibit long-term binding to muscarinic receptors in the salivary gland.[Experiment II] : Following the oral administration of Oxy, there was a significant increase in dissociation constant (K_d) for specific [N-methyl-^3H] scopolamine (NMS) binding in urinary bladder, submaxillary gland, heart and colon of rats compared with the value of control rats, and a concomitant reduction of maximal number of binding sites (B_<max>) only in submaxillary gland and heart. Such increase in K_d value in each tissue was seen at 1 and 3 hr after oral administration of Oxy, but not at 12 and 24 hr. In contrast, a significant reduction of B_<max> value in submaxillary gland and heart was maintained for at least 24 hr. Transdermal application of MM-801 for 2-48 hr caused a significant increase in K_d value for [^3H] NMS binding in bladder, submaxillary gland, heart and colon of rats, and there was little reduction of B_<max> value in each tissue. The increment of K_d value increased with the application time of MM-801, being maximal at 12 hr later. These data suggest that the transdermally administered Oxy (MM-801) binds significantly to the muscarinic receptor in urinary bladder of rats and the binding to the receptor in submaxillary gland is easily reversible by this TTS but not by the oral administration. The present study may provide a rationale for the usefulness of transdermal application of Oxy in the therapy of DI. Less

抗胆碱能药物如丙草碱和奥昔布宁（Oxy）被广泛用于治疗排尿和急迫性尿失禁。然而，这些药物的使用往往受到全身副作用的限制，如口服时经常发生口干，而且作用时间短。为了开发治疗DI的有效药物，我们研究了口服丙丙胺和奥昔布宁以及经皮给药氧氧（MM-801）后大鼠组织中毒蕈碱受体的结合情况。[实验一]：口服奥昔布宁引起大鼠膀胱、前列腺、颌下腺、心脏和大脑皮层特异性(-)-[^3H]QNB结合的表观解离常数（K_d）与各控制值相比显著升高。在这些大鼠的颌下腺中，(-)-[^3H]QNB结合的最大结合位点（B_<max>）减少。大鼠膀胱等组织中(-)-[^3H] QNB结合的K_d值显著增加，前列腺、心脏和颌下腺的K_d值增加更大。另一方面，与奥昔布宁不同，口服丙丙胺对(-)-[^3H] QNB在颌下腺结合的B_<max>值的降低非常小。总之，本研究表明，口服奥施布宁和丙丙碱后，与膀胱等组织中的毒蕈碱受体显著结合，奥施布宁似乎与唾液腺中的毒蕈碱受体长期结合。[实验二]：口服氧氧后，大鼠膀胱、下颌骨腺、心脏和结肠中特异性[n -甲基-^3H]东莨菪碱（NMS）结合的解离常数（K_d）与对照大鼠相比显著增加，同时仅上颌下腺和心脏中最大结合位点数（B_<max>）减少。口服氧合酮后1和3小时各组织的K_d值均有增加，但12和24小时无增加。相比之下，上颌下腺和心脏的B_<max>值的显著降低可维持至少24小时。MM-801经皮作用2 ~ 48小时后，大鼠膀胱、颌下腺、心脏和结肠[^3H] NMS结合的K_d值显著升高，各组织B_<max>值略有降低。K_d值随MM-801施用时间的增加而增加，在12 h后达到最大值。这些数据表明，经皮给药氧氧氧（MM-801）与大鼠膀胱毒蕈碱受体结合显著，且与颌下腺受体的结合容易被TTS逆转，而口服给药则不可逆。本研究可能为经皮应用氧氧治疗DI的有效性提供理论依据。少

项目成果

Oki,T.,Yamada,S.,Tohma,A.,Kimura,R.: "Muscarinic receptor binding characteristics in rat tissues after oral administration of oxybutynin and propiverine"Biol.Pharm.Bull.. (in press).

Oki,T.、Yamada,S.、Tohma,A.、Kimura,R.：“口服奥昔布宁和丙哌维林后大鼠组织中毒蕈碱受体的结合特征”Biol.Pharm.Bull..（出版中）。

隠岐知美,山田静雄 他: "尿失禁・頻尿治療薬、オキシブチニンの経皮吸収製剤のムスカリン性受容体結合動態"Progress in Drug Delivery System. IX. 51-60 (2000)

Tomomi Oki，Shizuo Yamada 等人：“奥昔布宁透皮制剂的毒蕈碱受体结合动力学，一种治疗尿失禁和尿频的药物”，药物输送系统进展 51-60 (2000)。

Oki, T., Yamada, S., Toma, A., Kimura, R., Kawashima, A.and Uchida, M.: "Muscarinic receptor binding of transdermally administered oxybutynin in treatment of detrusor instability."Prog.Drug Deliv.System. IX. 51-60 (2000)

Oki, T.、Yamada, S.、Toma, A.、Kimura, R.、Kawashima, A. 和 Uchida, M.：“经皮施用奥昔布宁的毒蕈碱受体结合治疗逼尿肌不稳定。”Prog.Drug Deliv。

Oki, T., Yamada, S., Tohma A.and Kimura, R.: "Muscarinic receptor binding characteristics in rat tissues after oral administration of oxybutynin and propiverine."Biol.Pharm.Bull. (in press).

Oki, T.、Yamada, S.、Tohma A. 和 Kimura, R.：“口服奥昔布宁和丙哌维林后大鼠组织中毒蕈碱受体的结合特征。”Biol.Pharm.Bull。