Progesterone

Progesterone undergoes rapid, extensive metabolism, principally in the liver but also in the brain and other tissues, and oral administration exposes it to substantial first-pass metabolism. Its main pathway involves sequential reduction by 5α- and 5β-reductases and 3α-, 3β-, 20α-, and 20β-hydroxysteroid dehydrogenases, followed by glucuronidation or sulfation. Smaller pathways involve hydroxylation by CYP17A1, CYP21A2, CYP11B1, and CYP11B2; CYP3A4 accounts for approximately 70% of P450-mediated metabolism, although P450 pathways appear to contribute only a small part of overall metabolism. Progesterone is also listed as a substrate of CYP1A1, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and CYP3A7, an inhibitor of CYP2C19, CYP2C9, CYP3A, and CYP3A7, and an inducer of CYP2A6 and CYP3A4. Hepatic enzyme induction is particularly relevant at the elevated concentrations of pregnancy. Approximately 96-99% is bound to serum proteins, primarily albumin and transcortin.⁴ Conjugated metabolites are eliminated mainly in urine, with additional biliary excretion, intestinal metabolism, enterohepatic recycling, and fecal elimination. Crinone vaginal gel has a progesterone absorption half-life of approximately 25 to 50 hours and an elimination half-life of 5 to 20 minutes.⁶ Reported apparent clearance is 106 ± 15 L/h with once-daily intramuscular administration.