Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri 63110, USA.
Anesthesiology. 2011 Dec;115(6):1251-60. doi: 10.1097/ALN.0b013e318238fea0.
The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine.
Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing.
Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation.
Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.
长效高亲和力阿片类药物丁丙诺啡具有复杂的药理学特性，包括在镇痛和呼吸抑制方面存在“天花板效应”。主要代谢物去甲丁丙诺啡、丁丙诺啡-3-葡萄糖醛酸苷和去甲丁丙诺啡-3-葡萄糖醛酸苷的血浆浓度与母体药物相当或超过母体药物。丁丙诺啡葡萄糖醛酸代谢物的药理学特性尚不清楚。本研究旨在确定两种葡萄糖醛酸代谢物与丁丙诺啡和去甲丁丙诺啡的结合和药理活性。
使用放射性配体结合法测定葡萄糖醛酸代谢物与人类μ、κ和δ阿片和孤啡肽受体的结合亲和力。在瑞士韦伯斯特小鼠体内评估常见阿片类药物的作用。使用尾部闪烁试验评估镇痛作用，使用非束缚性全身 plethysmography 测量呼吸作用，使用开放场试验测量运动抑制来评估镇静作用。
丁丙诺啡-3-葡萄糖醛酸对人类μ（Ki [抑制常数] = 4.9 ± 2.7 pM）、δ（Ki = 270 ± 0.4 nM）和孤啡肽（Ki = 36 ± 0.3 μM）受体具有高亲和力，但对κ受体没有亲和力。去甲丁丙诺啡-3-葡萄糖醛酸对人类κ（Ki = 300 ± 0.5 nM）和孤啡肽（Ki = 18 ± 0.2 μM）受体具有亲和力，但对μ或δ受体没有亲和力。在测试剂量下，丁丙诺啡-3-葡萄糖醛酸具有较小的镇痛作用。两种葡萄糖醛酸代谢物均未显著影响呼吸频率，但去甲丁丙诺啡-3-葡萄糖醛酸降低了潮气量。去甲丁丙诺啡-3-葡萄糖醛酸还引起镇静作用。
丁丙诺啡的两种葡萄糖醛酸代谢物在与代谢物暴露相关的剂量下具有生物活性，而代谢物暴露发生在丁丙诺啡之后。葡萄糖醛酸苷的活性可能对丁丙诺啡的整体药理学特性有贡献。
