Misra A L, Pontani R B, Vadlamani N L, Mulé S J
J Pharmacol Exp Ther. 1976 Feb;196(2):257-68.
A sensitive method is described for the estimation of [14C]naloxone in biological materials. After a 1 mg/kg s.c. dose of [14C]naloxone to male Wistar rats, mean peak levels of drug in brain (506 ng/g) and plasma (119 ng/ml) were attained within 15 minutes. No persistence of drug in brain was observed at this dose. After a 10 mg/kg s.c. dose, the peak levels of naloxone in brain and plasma were 4.31 mug/g and 1.27 mug/ml, respectively, and extensive localization of extractable free drug and its minor metabolite, naloxol, occurred in tissues with high levels in kidney, spleen, lung, heart, skeletal muscle and somewhat lower concentration in the liver. The T1/2 of naloxone and nalorphine in rat brain and plasma with 1 and 10 mg/kg s.c. doses was 0.4 hour. With a 10 mg/kg dose, significant amounts of radioactivity persisted in tissues but not in plasma 96 hours after injection. The brain/plasma ratios and degree of plasma-protein binding were significantly higher for naloxone as compared to nalorphine. The amounts of free naloxone excreted as a percentage of the dose in urine and feces 96 hours after injection of the 10 mg/kg s.c. dose were 4.1 and 3.9 (for nalorphine 4.7 and 8.3); conjugated drug 15.4 and 1.2 (for nalorphine 13 and 0.9); total radioactivity 43.3 and 20.9 (for nalorphine 34.8 and 19.2), respectively. Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. Rapid metabolism of naloxone and rapid elimination are important factors in its short duration of action. Possible relevance of these observations on differential antagonistic properties of these two antagonists are discussed.
本文描述了一种用于测定生物材料中[14C]纳洛酮的灵敏方法。给雄性Wistar大鼠皮下注射1mg/kg的[14C]纳洛酮后，15分钟内脑内（506ng/g）和血浆（119ng/ml）中的药物平均峰值水平达到最高。在此剂量下，未观察到药物在脑内持续存在。皮下注射10mg/kg剂量后，脑和血浆中纳洛酮的峰值水平分别为4.31μg/g和1.27μg/ml，可提取的游离药物及其次要代谢产物纳洛醇在肾脏、脾脏、肺、心脏、骨骼肌等组织中大量分布，在肝脏中的浓度略低。皮下注射1mg/kg和10mg/kg剂量后，大鼠脑和血浆中纳洛酮和纳洛芬的半衰期为0.4小时。注射10mg/kg剂量后96小时，大量放射性在组织中持续存在，但在血浆中未持续存在。与纳洛芬相比，纳洛酮的脑/血浆比值和血浆蛋白结合程度显著更高。皮下注射10mg/kg剂量后96小时，尿液和粪便中以剂量百分比形式排泄的游离纳洛酮量分别为4.1和3.9（纳洛芬为4.7和8.3）；结合型药物分别为15.4和1.2（纳洛芬为13和0.9）；总放射性分别为43.3和20.9（纳洛芬为34.8和19.2）。纳洛酮-3-葡萄糖醛酸苷（主要）、3-硫酸盐（次要）、纳洛醇和结合型纳洛醇（次要）、7,8-二氢-14-羟基去甲吗啡、7,8-二氢-14-羟基去甲吗啡及其结合物被证明是纳洛酮的代谢产物。此外，还获得了两种极性羟基化代谢产物（推测羟基化发生在17-侧链或芳环的2位）的初步证据。在脑中也观察到了7,8-二氢-14-羟基去甲吗啡酮和两种极性代谢产物。纳洛酮的快速代谢和快速消除是其作用持续时间短的重要因素。本文讨论了这些观察结果与这两种拮抗剂不同拮抗特性的可能相关性。
