Yasuhara M, Levy G
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst.
J Pharmacol Exp Ther. 1988 Jul;246(1):165-9.
The purpose of this investigation was to determine whether the pharmacodynamics of the centrally acting skeletal muscle relaxants zoxazolamine (ZOX) and chlorzoxazone (CZX) are altered in renal failure. Male Lewis rats with renal failure due to bilateral ligation of ureters and sham-operated controls (ZOX and CZX), as well as rats with uranyl nitrate-induced renal dysfunction and saline-injected controls (ZOX only), received an infusion of ZOX or CZX until onset of loss of righting reflex. Drug concentrations in serum, brain and cerebrospinal fluid at that time were substantially lower in animals with renal failure or dysfunction than in normal controls. The ZOX concentrations in the cerebrospinal fluid correlated negatively with indices of renal function (serum creatinine and urea concentrations). Administration of a concentrated dialyzate of serum from rats with uranyl nitrate-induced renal dysfunction to normal animals also decreased the concentrations of ZOX at onset of loss of righting reflex. Thus, the sensitivity of the central nervous system of rats to the depressant action of ZOX and CZX is significantly increased by renal failure. This effect appears to be mediated, at least in part, by an endogenous, dialyzable substance that accumulates in the blood of rats with impaired renal function.
本研究的目的是确定中枢性骨骼肌松弛剂唑沙宗（ZOX）和氯唑沙宗（CZX）的药效学在肾衰竭时是否会发生改变。通过双侧输尿管结扎造成肾衰竭的雄性Lewis大鼠和假手术对照组（ZOX和CZX），以及用硝酸铀酰诱导肾功能不全的大鼠和注射生理盐水的对照组（仅ZOX），输注ZOX或CZX直至翻正反射消失。此时，肾衰竭或功能不全动物的血清、脑和脑脊液中的药物浓度显著低于正常对照组。脑脊液中的ZOX浓度与肾功能指标（血清肌酐和尿素浓度）呈负相关。将硝酸铀酰诱导的肾功能不全大鼠的血清浓缩透析液给予正常动物，也会降低翻正反射消失时ZOX的浓度。因此，肾衰竭会显著增加大鼠中枢神经系统对ZOX和CZX抑制作用的敏感性。这种效应似乎至少部分是由一种内源性、可透析的物质介导的，该物质在肾功能受损的大鼠血液中蓄积。
