Dydrogesterone metabolism in human liver by aldo-keto reductases and cytochrome P450 enzymes

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Matthias OlbrichKatsuhiro Mihara

Abstract

1. The metabolism of dydrogesterone was investigated in human liver cytosol (HLC) and human liver microsomes (HLM). Enzymes involved in dydrogesterone metabolism were identified and their relative contributions were estimated. 2. Dydrogesterone clearance was clearly higher in HLC compared to HLM. The major active metabolite 20α-dihydrodydrogesterone (20α-DHD) was only produced in HLC. 3. The formation of 20α-DHD by cytosolic aldo-keto reductase 1C (AKR1C) was confirmed with isoenzyme-specific AKR inhibitors. 4. Using recombinantly expressed human cytochrome P450 (CYP) isoenzymes, dydrogesterone was shown to be metabolically transformed by CYP3A4 and CYP2C19. 5. A clear contribution of CYP3A4 to microsomal metabolism of dydrogesterone was demonstrated with HLM and isoenzyme-specific CYP inhibitors, and confirmed by a significant correlation between dydrogesterone clearance and CYP3A4 activity. 6. Contribution of CYP2C19 was shown to be clearly less than CYP3A4 and restricted to a small group of human individuals with very high CYP2C19 activity. Therefore, it is expected that CYP2C19 genetic variations will not affect dydrogesterone pharmacokinetics in man. 7. In conclusion, dydrogesterone metabolism in the liver is dominated pri...Continue Reading

References

Nov 1, 1989·The Journal of Clinical Investigation·S H Mellon, W L Miller
Mar 1, 1982·The American Journal of Physiology·C R Ashmore
Jan 1, 1980·European Journal of Drug Metabolism and Pharmacokinetics·P H van AmsterdamH de Bree
Nov 5, 1997·Archives of Biochemistry and Biophysics·H Yamazaki, T Shimada
Sep 12, 2002·Clinical Pharmacokinetics·Zeruesenay DestaDavid A Flockhart
Sep 7, 2006·Endocrine-related Cancer·John P Wiebe
Dec 6, 2007·Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology·Prakash TrivediSonia Malik
Oct 23, 2008·Journal of the American College of Cardiology·Anthony N DeMaria
Oct 20, 2009·Maturitas·Alfred O MueckKai-J Bühling
Dec 25, 2010·Chemico-biological Interactions·N BeraničT Lanišnik Rižner
Nov 6, 2013·Steroids·Tea Lanišnik Rižner, Trevor M Penning

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Citations

Jun 25, 2016·Journal of Molecular Endocrinology·Silvia GiattiMarzia Pesaresi

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