A liquid chromatographic-electrospray ionization-tandem mass spectrometric method for determination of buprenorphine, its metabolite, norBuprenorphine, and a coformulant, naloxone, that is suitable for in vivo and in vitro metabolism studies
A liquid chromatographic-electrospray ionization-tandem mass spectrometric method for determination of buprenorphine, its metabolite, norBuprenorphine, and a coformulant, naloxone, that is suitable for in vivo and in vitro metabolism studies
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DOI：
10.1006/abio.2002.5673
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发表时间：
2002-07-01
影响因子：
2.9
通讯作者：
Foltz, RL
中科院分区：
文献类型：
--
作者：
Moody, DE;Slawson, MH;Foltz, RL
已开发并验证了液相色谱-电喷雾电离-串联质谱法用于测定抗滥用药物丁丙诺啡、其主要代谢产物去甲丁丙诺啡和拟定复方制剂纳洛酮。该方法使用氘代内标和简单的液-液萃取。质谱法采用选择的反应监测，对丁丙诺啡、[H-2（4）]丁丙诺啡、降丁丙诺啡、[H-2（9）]降丁丙诺啡、纳洛酮和内标物[H-2（3）]纳洛酮的m/z跃迁进行监测，m/z分别为468 - 396、472 - 400、414 - 101、423 - 110、328 - 310和345 - 327。在0.1 - 10 ng/ml的动态范围内，该方法具有准确度和精密度。人血浆中所有分析物在室温下储存长达24 h和3次冻融循环后均保持稳定。复溶浸提液在-20 ℃下可稳定长达3天。在接受8 mg丁丙诺啡和2 mg纳洛酮舌下片剂的人类受试者中，检测到丁丙诺啡和去甲丁丙诺啡长达24 h，分别在1和1.5 h达到最大浓度。丁丙诺啡和去甲丁丙诺啡的最大浓度范围分别为2.2至2.8和1.5至2.4 ng/ml（即，约为6 nM）。该方法检测了与5-82 nM丁丙诺啡孵育的人肝微粒体中的降丁丙诺啡形成，其涵盖了治疗血浆浓度范围。当cDNA表达的P450与21 nM丁丙诺啡孵育时，如前所述，检测到P450 3A 4的降丁丙诺啡形成，但也检测到3A 5、3A 7和2C 8的降丁丙诺啡形成。丁丙诺啡的利用率通常超过降丁丙诺啡的形成，表明P450 2C 18、2C 19、2D 6和2 E1也可能参与丁丙诺啡代谢为其他产物。这些结果表明，该方法适用于丁丙诺啡代谢为去甲丁丙诺啡的体内和体外研究。(C)2002 Elsevier Science（美国）。
A liquid chromatographic-electrospray ionization-tandem mass spectrometric method has been developed and validated for determination of the antiabuse medication, buprenorphine, its primary metabolite, norbuprenorphine, and a proposed coformulant, naloxone. The method uses deuterated internal standards and a simple liquid-liquid extraction. Mass spectrometry employed selected reaction monitoring of the transitions of m/z 468 to 396 for buprenorphine, 472 to 400 for [H-2(4)]buprenorphine, 414 to 101 for norbuprenorphine, 423 to 110 for [H-2(9)]norbuprenorphine, 328 to 310 for naloxone, and 345 to 327 for its internal standard, [H-2(3)]naltrexone. The method was accurate and precise across the dynamic range of 0.1 to 10 ng/ml. All analytes were stable in human plasma stored at room temperature for up to 24 h and after three freeze-thaw cycles. Reconstituted extracts were stable at -20degreesC for up to 3 days. In human subjects receiving a sublingual tablet of 8 mg buprenorphine and 2 mg naloxone, buprenorphine and norbuprenorphine were detected for up to 24 h with respective maximum concentrations at 1 and 1.5 h. Maximal concentrations ranged from 2.2 to 2.8 and 1.5 to 2.4 ng/ml for buprenorphine and norbuprenorphine, respectively (i.e., approximate to6 nM). The method detected norbuprenorphine formation in human liver microsomes incubated with 5-82 nM buprenorphine, which encompasses the therapeutic plasma concentration range. When cDNA-expressed P450s were incubated with 21 nM buprenorphine, norbuprenorphine formation was detected for P450s 3A4, as previously described, but also for 3A5, 3A7, and 2C8. Buprenorphine utilization generally exceeded norbuprenorphine formation, suggesting that P450s 2C18, 2C19,2D6, and 2E1 may also be involved in buprenorphine metabolism to other products. These results suggest this method is suitable for both in vivo and in vitro studies of buprenorphine metabolism to norbuprenorphine. (C) 2002 Elsevier Science (USA).