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

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Olbrich M, Weigl K, Kahler E, Mihara K

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

Xenobiotica. 2016 Oct;46(10):868-74. doi: 10.3109/00498254.2015.1134852. Epub 2016 Jan 21.

PubMed ID

26796435 [ View in PubMed

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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 20alpha-dihydrodydrogesterone (20alpha-DHD) was only produced in HLC. 3. The formation of 20alpha-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 primarily by cytosolic enzymes (particularly AKR1C) and secondarily by CYP3A4, with the former exclusively responsible for 20alpha-DHD formation.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dydrogesterone	Cytochrome P450 3A4	Protein	Humans	No	Substrate	Details