Poor and variable oral bioavailability of dimethandrolone (DMA), an investigational male hormonal contraceptive, is likely associated with UGT2B17 mediated first‐pass metabolism
Authors: Sharma Sheena , Mettu Vijaya Saradhi , Ahire Deepak , Basit Abdul , Lajoie Maria , Lee Min S. , Blithe Diana L. , Amory John K. , Wang Christina , Prasad Bhagwat 
Published: May 2022

Dimethandrolone (DMA), an active metabolite of dimethandrolone undecanoate (DMAU) is a novel derivative of 19‐nortestosterone that is undergoing clinical investigation as an experimental male hormonal contraceptive.1 However, poor and variable oral bioavailability of DMAU including dramatic food‐effect2 may decrease its potential use by oral route. Moreover, DMA to DMAU serum concentration ratios revealed that food significantly alters the first‐pass metabolism of DMAU or DMA (Fig. 1A). Thus, the objective of this study was to investigate intestinal and hepatic metabolism of the active metabolite, DMA, to understand its poor bioavailability. We first detected and elucidated the structures of DMA metabolites formed in human hepatocyte incubations and in serum samples after oral administration in men using nano‐liquid chromatography high‐resolution mass spectrometry. The accurate mass and the mass fragmentation data confirmed DMA (m/z 303.2318) analogues of androstenedione (m/z 301.2162) and glucuronide (m/z 479.2639) in the human hepatocyte incubation, however, only DMA‐glucuronide was detected in the serum samples following an oral dose of 400 mg DMAU. DMA‐glucuronide serum concentration was >100‐fold higher than DMA levels, revealing glucuronidation as the major elimination mechanism for DMA. The targeted metabolomics of DMA revealed that unlike testosterone, DMA is not metabolized by other androgen metabolizing enzymes such as aromatase and 5‐α‐ and 5‐β‐ reductases, likely due to the absence of the C19‐methyl group.3,4 Next, to identify UGT isoforms involved in DMA metabolism, thirteen clinically‐relevant UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17) were screened for their capacity to metabolize DMA. Only UGT2B17 and UGT1A9 were able to metabolize DMA to DMA‐glucuronide. Finally, since UGT2B17 is a highly variable enzyme (>3000‐fold variability) with highly prevalent gene deletion, an enzyme kinetic experiment was performed in human intestinal microsomes (HIM) samples with known UGT2B17 expression. The kinetics data revealed >200‐fold higher maximum reaction velocity (Vmax) in the high UGT2B17‐expressing HIM samples as compared to the null expressors (Fig. 1B). Proteomics‐informed modeling estimated the intestinal fractional contributions (fm) of UGT2B17 in DMA glucuronidation to be 0.996, 0.994, and 0.0 in the high, average, and null expressors of UGT2B17, respectively. These data suggest that genetic variations in UGT2B17 and its high‐intestinal abundance are the potential reasons for the variable first‐pass metabolism and oral pharmacokinetics of DMA, whereas UGT1A9, which is expressed in the liver and kidney, likely decreases fm, UGT2B17 in DMA metabolism after intramuscular dosing.

Refs.

1. Attardi B J (2010).

2. Ayoub R (2017).

3. Attardi B J (2008).

4. Han Y (2021).