中枢神经系统渗透势的综合临床评价antimuscarinic代理治疗膀胱过动症。

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Malhotra B, Callegari E,邦吉PJ,韦伯斯特R,芬纳KS, Kempshall年代,LaPerle杰,米歇尔•MC凯GG

中枢神经系统渗透势的综合临床评价antimuscarinic代理治疗膀胱过动症。

Br中国新药杂志。2011年8月,72(2):235 - 46所示。doi: 10.1111 / j.1365-2125.2011.03961.x。

PubMed ID
21392072 (在PubMed
]
文摘

已经知道是什么这个问题:本研究提供了膀胱过动症(OAB)显示antimuscarinic代理变量与副作用由中枢神经系统(CNS),这可能是老年人的特别关注。影响中枢神经系统功能与毒蕈碱的受体亚型选择性和代理穿过血脑屏障的能力,P-gp扮演一个角色在限制渗透。这研究补充说:这项研究提供了一个平行调查,中枢神经系统的渗透antimuscarinic OAB代理体内和评估的物理性质和渗透率单层细胞体外。这进一步增加了对角色的理解被动transcellular渗透率和P-gp决定中枢神经系统的渗透antimuscarinic OAB代理。它还使中枢神经系统副作用的比较OAB代理与中枢神经系统的临床前插入数据。目的:评估和比较的机制的中枢神经系统(CNS)的渗透antimuscarinic膀胱过动症(OAB)代理。方法:计算物理性质或从文学编译。老鼠服用5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin tolterodine或trospium皮下注射。1 h postdose、等离子体、大脑和脑脊液(CSF)浓度测定使用质/ MS分析。大脑和血浆蛋白结合测定体外。 Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS: Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 x 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 x 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 x 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS: Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.

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