Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (S.S., D.A., A.B., D.K.S., B.P.); The Lundquist Institute at Harbor UCLA Medical Center, Torrance, California (M.L., C.W.); Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (M.S.L., D.L.B.); Department of Medicine, University of Washington School of Medicine, Seattle, Washington (J.K.A.); and BioIVT, Halethorpe, Maryland (S.H.).
Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (S.S., D.A., A.B., D.K.S., B.P.); The Lundquist Institute at Harbor UCLA Medical Center, Torrance, California (M.L., C.W.); Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (M.S.L., D.L.B.); Department of Medicine, University of Washington School of Medicine, Seattle, Washington (J.K.A.); and BioIVT, Halethorpe, Maryland (S.H.)
Drug Metab Dispos. 2022 Dec;50(12):1493-1500. doi: 10.1124/dmd.122.001041. Epub 2022 Oct 2.
Dimethandrolone undecanoate (DMAU), an oral investigational male hormonal contraceptive, is a prodrug that is rapidly converted to its active metabolite, dimethandrolone (DMA). Poor and variable oral bioavailability of DMA after DMAU dosing is a critical challenge to develop it as an oral drug. The objective of our study was to elucidate the mechanisms of variable pharmacokinetics of DMA. We first identified DMA metabolites formed in vitro and in vivo in human hepatocyte incubation and serum samples following oral DMAU administration in men, respectively. The metabolite identification study revealed two metabolites, DMA-glucuronide (DMA-G; major) and the androstenedione analog of DMA (minor), in the hepatocyte incubations. After oral DMAU administration, only DMA-G was detected in serum, which was >100-fold compared with DMA levels, supporting glucuronidation as the major elimination mechanism for DMA. Next, 13 clinically relevant UDP-glucuronosyltransferase (UGT) enzymes were tested for their involvement in DMA-G formation, which revealed a major role of UDP-glucuronosyltransferase 2B17 (UGT2B17) isoform with a smaller contribution of UGT1A9 in DMA-G formation. These data were confirmed by dramatically higher DMA glucuronidation rates (>200- and sevenfold) in the high versus the null UGT2B17-expressing human intestinal and liver microsomes, respectively. Since human UGT2B17 is a highly variable enzyme with a 20%-80% gene deletion frequency, the in vitro data suggest a major role of UGT2B17 polymorphism on the first-pass metabolism of DMA. Further, considering DMA is a selective and sensitive UGT2B17 substrate, it could be used as a clinical probe of UGT2B17 activity. SIGNIFICANCE STATEMENT: Dimethandrolone (DMA) is an active metabolite of dimethandrolone undecanoate (DMAU), an investigational male hormonal contraceptive. Previous studies have indicated poor and inconsistent bioavailability of DMAU following oral administration. This study found that UDP-glucuronosyltransferase 2B17-mediated high intestinal first-pass metabolism is the key mechanism of variable DMA bioavailability.
十一酸双氢睾酮二甲酯（DMAU），一种口服的研究性男性激素避孕药，是一种前药，可迅速转化为其活性代谢物双氢睾酮（DMA）。在男性中口服 DMAU 后，DMA 的口服生物利用度较差且变化较大，这是将其开发为口服药物的一个关键挑战。我们研究的目的是阐明 DMA 药代动力学变化的机制。我们首先分别在人体肝细胞孵育和血清样本中鉴定了男性口服 DMAU 后体内和体外形成的 DMA 代谢物。代谢产物鉴定研究揭示了两种代谢物，DMA-葡萄糖醛酸苷（DMA-G；主要）和 DMA 的雄烯二酮类似物（次要），在肝细胞孵育中。口服 DMAU 后，仅在血清中检测到 DMA-G，其水平是 DMA 的 100 倍以上，支持葡萄糖醛酸化是 DMA 的主要消除机制。接下来，测试了 13 种临床相关的尿苷二磷酸-葡萄糖醛酸转移酶（UGT）酶是否参与 DMA-G 的形成，结果表明 UDP-葡萄糖醛酸转移酶 2B17（UGT2B17）同工型起主要作用，而 UGT1A9 对 DMA-G 的形成贡献较小。这些数据通过高表达 UGT2B17 的人肠和肝微粒体中的 DMA 葡萄糖醛酸化率分别显著提高（>200-和 7 倍）得到了证实。由于人类 UGT2B17 是一种高度可变的酶，其基因缺失频率为 20%-80%，体外数据表明 UGT2B17 多态性对 DMA 的首过代谢具有重要作用。此外，由于 DMA 是一种选择性和敏感的 UGT2B17 底物，它可以用作 UGT2B17 活性的临床探针。意义陈述：双氢睾酮（DMA）是十一酸双氢睾酮二甲酯（DMAU）的一种活性代谢物，DMAU 是一种研究性男性激素避孕药。先前的研究表明，口服给药后 DMAU 的生物利用度较差且不一致。本研究发现，UDP-葡萄糖醛酸转移酶 2B17 介导的肠道首过代谢是 DMA 生物利用度变化的关键机制。
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