Evidence map›Paper›PMID 36184078›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2022

Dimethandrolone, a Potential Male Contraceptive Pill, is Primarily Metabolized by the Highly Polymorphic UDP-Glucuronosyltransferase 2B17 Enzyme in Human Intestine and Liver.

Sheena Sharma, Deepak Ahire, Abdul Basit, Maria Lajoie, Christina Wang, Min S Lee, Diana L Blithe, John K Amory, Dilip K Singh, Scott Heyward and 1 more

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Article in Drug metabolism and disposition: the biological fate of chemicals, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
1.1field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 6 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Review
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 1 institution in 1 country.

Sheena SharmaDepartment 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.).
Deepak AhireDepartment 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.).ORCID 0000-0001-8537-6047
Abdul BasitDepartment 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.).
Maria LajoieDepartment 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.).
Christina WangDepartment 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.).
Min S LeeDepartment 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.).
Diana L BlitheDepartment 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.).
John K AmoryDepartment 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.).
Dilip K SinghDepartment 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.).
Scott HeywardDepartment 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.).ORCID 0000-0001-7805-3522
Bhagwat PrasadDepartment 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.) bhagwat.prasad@wsu.edu.ORCID 0000-0002-9090-0912
National Institutes of Health · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Contraceptive Agents, MaleGlucuronidesGlucuronosyltransferaseHumansIntestinesLiverMaleMicrosomes, LiverNandroloneUridine Diphosphate7alpha,11beta-dimethyl-19-nortestosteroneContraceptive Agents, MaleGlucuronidesGlucuronosyltransferaseNandroloneUridine Diphosphate

Identifiers

PMID36184078
PMCPMC9720754
OpenAlexW4299878852

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.