Department of Pharmacology, Wakayama Medical University, Wakayama-City, Wakayama 641-8509, Japan.
Neurosci Lett. 2013 Sep 27;552:98-102. doi: 10.1016/j.neulet.2013.07.040. Epub 2013 Aug 7.
Nor-binaltorphimine (nor-BNI) is kappa opioid receptor (KOR) antagonist with the extremely long duration in mice analgesic assay, in vivo. For the evaluation of long-lasting effect of nor-BNI, brain content and serum concentration of nor-BNI were quantified in comparison with those of naloxone (a short-acting non-specific opioid receptor antagonist) by high-performance liquid chromatography with electrochemical detector in mice. After concomitant administration (20 mg/kg, s.c.) of nor-BNI and naloxone, nor-BNI in brain and serum showed biphasic elimination, with a rapid phase for 0.75-4 h and a slow phase for 4-48 h. Elimination rate in brain was slower than that of serum. Naloxone in brain and serum was detected for 3 h and 4 h, respectively. The brain/serum ratio of nor-BNI gradually increased over 0.75-48 h, while that of naloxone rapidly declined. After concomitant administration (30 mg/kg, s.c.) of nor-BNI and naloxone, brain nor-BNI was detected in all mice from day 1 to day 21 and in two of six mice at day 28, while serum nor-BNI was detected in all mice at day 1, three of seven at day 3 and one of six at day 7. After that, serum nor-BNI was not detected. Naloxone in brain and serum was not detected at day 1. These results provide pharmacokinetic support for the long-lasting antagonistic effects of nor-BNI.
在体内小鼠镇痛试验中，去甲纳曲酮（nor-BNI）是一种κ阿片受体（KOR）拮抗剂，具有极长的作用持续时间。为了评估 nor-BNI 的长效作用，通过高效液相色谱电化学检测法比较了 nor-BNI 和纳洛酮（一种短效非特异性阿片受体拮抗剂）在小鼠中的脑含量和血清浓度。在同时给予 nor-BNI（20mg/kg，sc）和纳洛酮后，脑和血清中的 nor-BNI 呈双相消除，快速相为 0.75-4 h，缓慢相为 4-48 h。脑内消除速率比血清慢。脑内和血清中的纳洛酮分别检测到 3 h 和 4 h。脑/血清中 nor-BNI 的比值在 0.75-48 h 内逐渐增加，而纳洛酮的比值迅速下降。在同时给予 nor-BNI（30mg/kg，sc）和纳洛酮后，所有小鼠在第 1 天至第 21 天都检测到脑内 nor-BNI，6 只小鼠中有 2 只在第 28 天仍能检测到，而血清 nor-BNI 则在所有小鼠在第 1 天都能检测到，7 只中有 3 只在第 3 天，6 只中有 1 只在第 7 天仍能检测到。此后，血清 nor-BNI 未能检测到。脑内和血清中的纳洛酮在第 1 天都未能检测到。这些结果为 nor-BNI 的长效拮抗作用提供了药代动力学支持。
