TY - JOUR T1 - Dimethandrolone (DMA), a Potential Male Contraceptive Pill, is Primarily Metabolized by the Highly Polymorphic UGT2B17 Enzyme in Human Intestine and Liver JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.122.001041 SP - DMD-AR-2022-001041 AU - Sheena Sharma AU - Deepak Ahire AU - Abdul Basit AU - Maria Lajoie AU - Christina Wang AU - Min S. Lee AU - Diana L. Blithe AU - John K. Amory AU - Dilip K. Singh AU - Scott Heyward AU - Bhagwat Prasad Y1 - 2022/01/01 UR - http://dmd.aspetjournals.org/content/early/2022/10/02/dmd.122.001041.abstract N2 - Dimethandrolone undecanoate (DMAU), an oral investigational male hormonal contraceptive is a prodrug, which 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 (PK) 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 analogue of DMA (minor) in the hepatocyte incubations. After oral DMAU administration, only DMA-G was detected in serum, which was >100-fold compared to DMA levels, supporting glucuronidation as the major elimination mechanism for DMA. Next, thirteen clinically- relevant UDP-glucuronosyltransferase (UGT) enzymes were tested for their involvement in DMA-G formation, which revealed a major role of UGT2B17 isoform with a smaller contribution of UGT1A9 in DMA-G formation. These data were confirmed by dramatically higher DMA glucuronidation rates (>200- and >7-fold) 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. Our study found that UGT2B17-mediated high intestinal first-pass metabolism is the key mechanism of variable DMA bioavailability. ER -