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Abstract ID 97258 Poster Board 038 Despite the availability of effective female-centric contraceptives, millions of unintended pregnancies are reported annually.1 Recent developments in the realm of oral male contraceptives are viewed as promising steps to address this reproductive health challenge. The compound 11β-methyl-nortestosterone dodecylcarbonate (11β-MNTDC), a prodrug of 11β-MNT, is being developed as a hormonal male contraceptive.2 However, clinical data of oral 11β-MNTDC show poor and variable bioavailability, highlighting the need to investigate the mechanisms affecting its absorption into the systemic circulation.3 The specific aims of this study were to: i) identify biotransformation products of 11β-MNT and its prodrugs, and ii) characterize 'the isoforms of uridine 59-diphospho-glucuronosyltransferases (UGTs) involved in glucuronidation of 11β-MNT. To identify biotransformation products, 11β-MNT, 11β-MNTDC, and another prodrug (11β-MNT undecanoate or 11β-MNTU) were incubated in cryopreserved human hepatocytes (n = 4 donors) for 120 min. The reaction was quenched and analyzed by nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS). The HRMS data were processed using an optimized metabolomics approach with XCMS Online software. This analysis revealed seven biotransformation products of 11β-MNT, including two major metabolites, dehydrogenation and glucuronidation products (11β-MNTG) with >10% relative mass response and five minor metabolites with a relative mass response of 2>0.99) between 11β-MNTG formation and UGT2B17 protein abundance. Subsequent incubation of 11β-MNT and its prodrugs in S9 fractions of the human intestine (HIS9) and liver (HLS9) showed formation of the same two major metabolites identified in the hepatocyte incubation. Interestingly, 11β-MNTG was higher in HIS9 in comparison to that of the dehydrogenation product, which corresponds to the higher abundance of UGT2B17 in the intestine than in the liver. The reaction phenotyping data, using thirteen different recombinant UGT enzymes, confirmed that UGT2B17 plays a primary role (98%) in the formation of 11β-MNTG, with a minor role played by UGT1A4, 1A8, 1A9 and 2B7 (3 Funding source: National Institutes of Child Health and Human Development (Contract No. 75N94020D00003 awarded to SRI International)
Bachhav et al. (Mon,) studied this question.
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