INSERM U705, CNRS UMR8206, Université Paris Descartes, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, Paris, France.
Crit Care Med. 2012 Dec;40(12):3215-23. doi: 10.1097/CCM.0b013e318265680a.
Deaths due to asphyxia as well as following acute poisoning with severe respiratory depression have been attributed to buprenorphine in opioid abusers. However, in human and animal studies, buprenorphine exhibited ceiling respiratory effects, whereas its metabolite, norbuprenorphine, was assessed as being a potent respiratory depressor in rodents. Recently, norbuprenorphine, in contrast to buprenorphine, was shown in vitro to be a substrate of human P-glycoprotein, a drug-transporter involved in all steps of pharmacokinetics including transport at the blood-brain barrier. Our objectives were to assess P-glycoprotein involvement in norbuprenorphine transport in vivo and study its role in the modulation of buprenorphine-related respiratory effects in mice.
University-affiliated research laboratory, INSERM U705, Paris, France.
Wild-type and P-glycoprotein knockout female Friend virus B-type mice.
Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion.
Norbuprenorphine(≥ 1 mg/kg) and to a lesser extent buprenorphine (≥ 10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (TI) and expiratory times (TE). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on TI (p < .01) and TE (p < .05) and norbuprenorphine-related effects on minute volume (VE, p < .05), TI, and TE (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on VE (p < .01), TE (p < .001), and TI (p < .05) and norbuprenorphine-related effects on VE (p < .05) and TI (p < .001) were significantly enhanced. Plasma norbuprenorphine concentrations were significantly increased in PSC833-treated mice (p < .001), supporting a P-glycoprotein role in norbuprenorphine pharmacokinetics. Brain norbuprenorphine efflux was significantly reduced in PSC833-treated and P-glycoprotein-knockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood-brain barrier.
P-glycoprotein plays a key-protective role in buprenorphine-related respiratory effects, by allowing norbuprenorphine efflux at the blood-brain barrier. Our findings suggest a major role for drug-drug interactions that lead to P-glycoprotein inhibition in buprenorphine-associated fatalities and respiratory depression.
阿片类药物滥用者因丁丙诺啡导致窒息死亡和急性中毒伴严重呼吸抑制。然而，在人体和动物研究中，丁丙诺啡表现出呼吸抑制的“天花板”效应，而其代谢物去甲丁丙诺啡被评估为在啮齿动物中具有很强的呼吸抑制作用。最近，去甲丁丙诺啡与丁丙诺啡相反，在体外被证明是人类 P 糖蛋白的底物，P 糖蛋白是一种参与包括血脑屏障转运在内的所有药代动力学步骤的药物转运体。我们的目的是评估去甲丁丙诺啡在体内的 P 糖蛋白转运，并研究其在调节小鼠丁丙诺啡相关呼吸作用中的作用。
法国巴黎 INSERM U705 大学附属研究实验室。
野生型和 P 糖蛋白敲除雌性 Friend 病毒 B 型小鼠。
使用体积描记法研究呼吸作用，使用原位脑灌流研究 P 糖蛋白在血脑屏障中的作用。
去甲丁丙诺啡（≥ 1mg/kg）和较小程度的丁丙诺啡（≥ 10mg/kg）导致剂量依赖性呼吸抑制，包括吸气时间（TI）和呼气时间（TE）增加。强效 P 糖蛋白抑制剂 PSC833 显著增强了丁丙诺啡相关作用对 TI（p <.01）和 TE（p <.05）以及去甲丁丙诺啡相关作用对分钟通气量（VE，p <.05）、TI 和 TE（p <.001）的影响。在 P 糖蛋白敲除小鼠中，丁丙诺啡相关作用对 VE（p <.01）、TE（p <.001）和 TI（p <.05）以及去甲丁丙诺啡相关作用对 VE（p <.05）和 TI（p <.001）的影响明显增强。PSC833 处理小鼠的血浆去甲丁丙诺啡浓度显著升高（p <.001），支持 P 糖蛋白在去甲丁丙诺啡药代动力学中的作用。PSC833 处理和 P 糖蛋白敲除小鼠的脑去甲丁丙诺啡外排明显减少（p <.001），支持 P 糖蛋白介导的血脑屏障去甲丁丙诺啡转运。
P 糖蛋白通过允许去甲丁丙诺啡从血脑屏障流出，在丁丙诺啡相关呼吸作用中发挥关键的保护作用。我们的发现表明，药物-药物相互作用导致 P 糖蛋白抑制在丁丙诺啡相关的致命性和呼吸抑制中起主要作用。
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