Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry.
Simultaneous pharmacokinetic and pharmacodynamic analysis of 5α-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry.
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DOI：
10.1016/j.talanta.2014.07.087
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发表时间：
2015-01
期刊：
影响因子：
6.1
通讯作者：
Andrew, Ruth
中科院分区：
文献类型：
--
作者：
Upreti, Rita;Naredo, Gregorio;Faqehi, Abdullah M. M.;Hughes, Katherine A.;Stewart, Laurence H.;Walker, Brian R.;Homer, Natalie Z. M.;Andrew, Ruth
关键词：
当药效学生物标志物可用于评估缓解时，可使用5α-还原酶抑制剂非那雄胺和度他雄胺治疗良性前列腺增生和前列腺癌。开发了一种新方法，使用ABSciex QTRAP® 5500和沃茨Acquity™ UPLC，通过液相色谱串联质谱法同时测定5α-还原酶（睾酮、5α-二氢睾酮（DHT）、雄烯二酮）以及非那雄胺和度他雄胺的底物和产物。通过固相萃取（Oasis® HLB）从血清（500 µL）中提取分析物，13 C3标记的雄激素和d9-finlidde作为内标物。在Kinetex C18色谱柱（150×3 mm，2.6 µm）上分离分析物，梯度运行19 min。确保了分析物与天然存在的异构体和质量+2同位素异构体的时间分辨率。质子化的分子离子检测在大气压化学电离模式和源条件优化的DHT，最丰富的分析物。多反应监测如下：睾酮（m/z 289→97）、DHT（m/z 291→255）、雄烯二酮（m/z 287→97）、度他雄胺（m/z 529→461）、非那雄胺（m/z 373→317）。验证参数（试验内和试验间精密度和准确度、线性、定量限）在可接受范围内，生物提取物可稳定储存28天。最后，该方法被用于接受非那雄胺或度他雄胺治疗的男性;这两种药物均降低了DHT水平，而且底物浓度增加。5α-还原酶抑制剂与酶底物和产物的同时分析。药代动力学/药效学联合分析。雄激素、度他雄胺和非那雄胺的快速、灵敏和稳健分析。
Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP® 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis® HLB), with 13C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150×3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289→97), DHT (m/z 291→255), androstenedione (m/z 287→97), dutasteride (m/z 529→461), finasteride (m/z 373→317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased. Simultaneous analysis of 5α-reductase inhibitors with enzyme substrates and products. Combined pharmacokinetic/pharmacodynamic analysis. Rapid, sensitive and robust analysis of androgens, dutasteride and finasteride.
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影响因子：
5
作者：
Harwood, D. Tim;Handelsman, David J.
通讯作者：
Handelsman, David J.
影响因子：
5.8
作者：
Kulle, A. E.;Riepe, F. G.;Holterhus, P. M.
通讯作者：
Holterhus, P. M.
DOI：
10.1016/0378-4347(94)00461-d
发表时间：
1995-01-20
期刊：
JOURNAL OF CHROMATOGRAPHY B-BIOMEDICAL APPLICATIONS
影响因子：
--
作者：
LEGRAND, C;DOUSSET, B;NABET, P
通讯作者：
NABET, P
影响因子：
2.7
作者：
Licea-Perez, Hermes;Wang, Sherry;Yang, Eric
通讯作者：
Yang, Eric
影响因子：
9.3
作者：
Kushnir, Mark M.;Blamires, Takara;Meikle, A. Wayne
通讯作者：
Meikle, A. Wayne