Bachhav Namrata, Singh Dilip Kumar, Blithe Diana L, Lee Min S, Prasad Bhagwat
College of Pharmacy and Pharmaceutical Sciences, Washington State University (WSU), Spokane, WA 99202, USA.
Contraceptive Development Program, Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 1 Center Dr, Bethesda, MD 20892, USA.
Pharmaceutics. 2024 Aug 2;16(8):1032. doi: 10.3390/pharmaceutics16081032.
11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is a prodrug of 11β-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11β-MNTDC exhibits an ~200-fold lower serum concentration of 11β-MNT compared to 11β-MNTDC, resulting in the poor bioavailability of 11β-MNT. To elucidate the role of the first-pass metabolism of 11β-MNT in its poor bioavailability, we determined the biotransformation products of 11β-MNT and its prodrugs in human in vitro models. 11β-MNT and its two prodrugs 11β-MNTDC and 11β-MNT undecanoate (11β-MNTU) were incubated in cryopreserved human hepatocytes (HHs) and subjected to liquid chromatography-high resolution tandem mass spectrometry analysis, which identified ten 11β-MNT biotransformation products with dehydrogenated and glucuronidation (11β-MNTG) metabolites being the major metabolites. However, 11β-MNTG formation is highly variable and prevalent in human intestinal S9 fractions. A reaction phenotyping study of 11β-MNT using thirteen recombinant UDP-glucuronosyltransferase (UGT) enzymes confirmed the major role of UGT2B17 in 11β-MNTG formation. This was further supported by a strong correlation (R > 0.78) between 11β-MNTG and UGT2B17 abundance in human intestinal microsomes, human liver microsomes, and HH systems. These results suggest that 11β-MNT and its prodrugs are rapidly metabolized to 11β-MNTG by the highly polymorphic intestinal UGT2B17, which may explain the poor and variable bioavailability of the drug.
11β-甲基-19-去甲睾酮十二烷基碳酸酯（11β-MNTDC）是11β-MNT的前体药物，在临床开发中被视为一种有前景的男性口服避孕药候选药物。然而，与11β-MNTDC相比，口服11β-MNTDC后11β-MNT的血清浓度低约200倍，导致11β-MNT的生物利用度较差。为了阐明11β-MNT首过代谢在其低生物利用度中的作用，我们在人源体外模型中确定了11β-MNT及其前体药物的生物转化产物。11β-MNT及其两种前体药物11β-MNTDC和11β-去甲睾酮十一酸酯（11β-MNTU）在冻存的人肝细胞（HHs）中孵育，并进行液相色谱-高分辨率串联质谱分析，该分析鉴定出十种11β-MNT生物转化产物，其中脱氢和葡萄糖醛酸化（11β-MNTG）代谢物是主要代谢物。然而，11β-MNTG的形成在人肠S9组分中高度可变且普遍存在。使用十三种重组尿苷二磷酸葡萄糖醛酸基转移酶（UGT）对11β-MNT进行的反应表型研究证实了UGT2B17在11β-MNTG形成中的主要作用。人肠微粒体、人肝微粒体和HH系统中11β-MNTG与UGT2B17丰度之间的强相关性（R>0.78）进一步支持了这一点。这些结果表明，11β-MNT及其前体药物被高度多态性的肠道UGT2B17迅速代谢为11β-MNTG，这可能解释了该药物较差且可变的生物利用度。
