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首页> 外文期刊>Growth hormone and IGF research: Official journal of the Growth Hormone Research Society and the International IGF Research Society >Determination of LongR 3 -IGF-I, R 3 -IGF-I, Des1-3 IGF-I and their metabolites in human plasma samples by means of LC-MS
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Determination of LongR 3 -IGF-I, R 3 -IGF-I, Des1-3 IGF-I and their metabolites in human plasma samples by means of LC-MS

机译：通过LC-MS测定LONGR 3 -IGF-I，R 3 -IGF-I，DES1-3 IGF-I及其在人血浆样品中的代谢物

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Abstract According to the regulations of the World Anti-Doping Agency (WADA), growth promoting peptides such as the insulin-like growth factor-I (IGF-I) and its synthetic analogues belong to the class of prohibited compounds. While several assays to quantify endogenous IGF-I have been established, the potential misuse of synthetic analogues such as LongR 3 -IGF-I, R 3 -IGF-I and Des1-3-IGF-I remains a challenge and superior pharmacokinetic properties have been described for these analogues. Within the present study, it was demonstrated that the target peptides can be successfully detected in plasma samples by means of magnetic beads-based immunoaffinity purification and subsequent nanoscale liquid chromatographic separation with high resolution mass spectrometric detection. Noteworthy, the usage of a specific antibody for LongR 3 -IGF-I enables the determination in low ng/mL levels despite the presence of an enormous excess of endogenous human IGF-I. In addition, different metabolism studies ( in - vitro and in - vivo ) were performed using sophisticated strategies such as incubation with skin tissue microsomes, degradation in biological fluids (for all analogues), and administration to rats (for LongR 3 -IGF-I). Herewith, several C-and N-terminally truncated metabolites were identified and their relevancy was additionally confirmed by in - vivo experiments with rodents. Especially for LongR 3 -IGF-I, a metabolite ((Des1-11)-LongR 3 -IGF-I) was identified that prolonged the detectability in - vivo by a factor of approximately 2. The method was validated for qualitative interpretation considering the parameters specificity, identification capability, recovery (26–60%), limit of detection (0.5 ng/mL), imprecision ( 25%), linearity, stability, and matrix effects. A stable isotope labelled ( 15 N)-IGF-I was used as internal standard to control all sample preparation steps. Highlights ? Validated immunopurification assisted LC-HRMS method for IGF-I analogues ? In-vitro metabolism using skin tissue microsomes ? New longterm metabolites for doping controls identified in-vitro and in-vivo ? Increased sensitivity in sub-ng/mL range ]]>
机译：摘要根据世界反兴奋剂机构（WADA）的规定，增长促进肽等胰岛素样生长因子-1（IGF-1）及其合成类似物属于禁止化合物的类别。虽然已经建立了几种测量内源IGF-I的测定，但潜在的滥用合成类似物如Longr 3 -igf-i，R 3 -igf-i和des1-3-IGF-I仍然是一个挑战和优异的药代动力学性质已经描述了这些类似物。在本研究中，证明靶肽可以通过基于磁珠的免疫亲和纯化和随后的纳米级液相色谱分离在等离子体样品中成功地检测到血浆样品中。值得注意的是，尽管存在巨大过量的人IGF-1，但是对于Longr 3 -igf-i的特异性抗体的用途能够确定低Ng / ml水平。此外，使用复杂的策略进行不同的代谢研究（体外和体内），例如与皮肤组织微粒体孵育，生物液中的降解（对于所有类似物），以及给大鼠（用于Longr 3 -igf-i ）。在此，鉴定了几种C-and N-末端截短的代谢物，并且通过啮齿动物的体内实验另外证实了它们的相关性。特别是对于LONGR 3 -IGF-I，鉴定了代谢物（（DES1-11）-LONGR 3 -IGF-I），其延长了延长的可检测性约为约2.考虑到定性解释的方法验证了该方法参数特异性，识别能力，恢复（26-60％），检测限（0.5ng / ml），不精确（＆ 25％），线性，稳定性和矩阵效应。标记的稳定同位素（15n）-igf-i用作内标以控制所有样品制备步骤。强调 ？验证免疫纯化辅助LC-HRMS方法用于IGF-I类似物？使用皮肤组织微粒体的体外代谢？新的Longterm代谢物用于鉴定在体外和体内掺杂对照的新代谢物？亚Ng / ml范围内的敏感性增加]]>

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