Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice

被引:49
作者
Alhaddad, Hisham [1 ]
Cisternino, Salvatore [1 ]
Decleves, Xavier [1 ]
Tournier, Nicolas [4 ]
Schlatter, Joel [3 ]
Chiadmi, Fouad
Risede, Patricia [1 ]
Smirnova, Maria [1 ]
Besengez, Capucine [1 ]
Scherrmann, Jean-Michel [1 ]
Baud, Frederic J. [1 ,2 ]
Megarbane, Bruno [1 ,2 ]
机构
[1] Univ Paris 05, Fac Pharm, CNRS UMR8206, INSERM U705, Paris, France
[2] Hop Lariboisiere, AP HP, F-75475 Paris, France
[3] Hop Jean Verdier, AP HP, Lab Toxicol, Bondy, France
[4] Serv Hosp Freder Joliot, I2BM, CEA, Orsay, France
关键词
buprenorphine; drug-drug interaction; in situ brain perfusion; knockout mice; norbuprenorphine; opioid; P-glycoprotein; plethysmography; respiratory depression; MULTIDRUG-RESISTANCE; INTESTINAL-ABSORPTION; HEALTHY-VOLUNTEERS; PERFUSION MODEL; DEFICIENT MICE; HUMAN-PLASMA; SDZ PSC-833; TRANSPORT; MORPHINE; RATS;
D O I
10.1097/CCM.0b013e318265680a
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Objectives: 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 bloodbrain 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. Setting: University-affiliated research laboratory, INSERM U705, Paris, France. Subjects: Wild-type and P-glycoprotein knockout female Friend virus B-type mice. Interventions: Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion. Measurements and Main Results: Norbuprenorphine(>= 1 mg/kg) and to a lesser extent buprenorphine (>= 10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (T-I) and expiratory times (T-E). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on T-I (p < .01) and T-E (p < .05) and norbuprenorphine-related effects on minute volume (V-E, p < .05), T-I, and T-E (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on V-E (p < .01), T-E (p < .001), and T-I (p < .05) and norbuprenorphine-related effects on V-E (p < .05) and T-I (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-glycoproteinknockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood-brain barrier. Conclusions: 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. (Crit Care Med 2012; 40:3215-3223)
引用
收藏
页码:3215 / 3223
页数:9
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