Drug–drug interaction and doping: Effect of non‐prohibited drugs on the urinary excretion profile of methandienone,Drug Testing and Analysis

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Drug–drug interaction and doping: Effect of non‐prohibited drugs on the urinary excretion profile of methandienone
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2018-07-01 , DOI: 10.1002/dta.2406
Monica Mazzarino ₁ , Franziska L. Khevenhüller-Metsch ₁ , Ilaria Fiacco ₁ , Maria Kristina Parr ₂ , Xavier de la Torre ₁ , Francesco Botrè _{1,

3}

Affiliation

The potential consequences of drug–drug interactions on the excretion profile of the anabolic androgenic steroid methandienone (17β‐hydroxy‐17α‐methylandrosta‐1,4‐dien‐3‐one) are discussed. More specifically, we have evaluated by in vitro and in vivo experiments the effects of 7 non‐prohibited drugs (fluconazole, ketoconazole, itraconazole, miconazole, fluoxetine, paroxetine, and nefazodone) on the main metabolic pathways of methandienone. These are selected among those most commonly used by the athletes. The in vitro assays were based on the use of human liver microsomes, specific recombinant enzyme isoforms of cytochrome P450 and uridine 5′‐diphospho‐glucuronosyl‐transferase. The in vivo study was performed by analyzing urines collected after the oral administration of methandienone with and without the co‐administration of ketoconazole. Methandienone and its metabolites were determined by liquid chromatography–mass spectrometry–based techniques after sample pretreatment including an enzymatic hydrolysis step (performed only for the investigation on phase II metabolism) and liquid/liquid extraction with t‐butyl methyl‐ether. The results from the in vitro experiments showed that the formation of the hydroxylated and dehydrogenated metabolites was significantly reduced in the presence of itraconazole, ketoconazole, miconazole and nefazodone, whereas the production of the 18‐nor‐hydroxylated metabolites and glucuronidation reactions was reduced significantly only in the presence of ketoconazole and miconazole. The analysis of the post‐administration samples confirmed the in vitro observations, validating the hypothesis that drug–drug interaction may cause significant alterations in the metabolic profile of banned drugs, making their detection during doping control tests more challenging.

中文翻译：

药物-药物相互作用和兴奋剂：非禁用药物对美满丁酮尿排泄曲线的影响

讨论了药物-药物相互作用对合成代谢雄激素类固醇美登酮（17β-羟基-17α-甲基雄甾烯-1,4-二烯-3-酮）排泄的潜在影响。更具体地说，我们已通过体外和体内实验评估了7种非禁用药物（氟康唑，酮康唑，伊曲康唑，咪康唑，氟西汀，帕罗西汀和奈法唑酮）对美达替尼的主要代谢途径的影响。这些是运动员最常使用的那些。在体外测定法基于使用人肝微粒体，细胞色素P450和尿苷5'-二磷酸-葡萄糖醛酸基转移酶的特异性重组酶同种型的。在体内这项研究是通过分析口服美德替尼酮与不合并酮康唑的情况下收集的尿液来进行的。样品预处理包括酶促水解步骤（仅用于II期代谢研究）和叔丁基甲基醚液/液萃取后，通过基于液相色谱-质谱法的技术测定甲硫酮及其代谢产物。体外结果实验表明，在伊曲康唑，酮康唑，咪康唑和奈法唑酮的存在下，羟基化和脱氢代谢物的形成显着减少，而18-去羟基化代谢物的生成和葡萄糖醛酸化反应仅在存在酮康唑和咪康唑。给药后样品的分析证实了体外观察，证实了以下假设：药物相互作用可能会导致被禁药物的代谢特征发生重大变化，这使得在兴奋剂对照试验中对其进行检测更具挑战性。

更新日期：2018-07-01

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