Effect of Polymorphisms in CYP2C9 and CYP2C19 on the Disposition, Safety and Metabolism of Progesterone Administrated Orally or Vaginally.

Introduction: Exogenous progesterone is prescribed for a variety of conditions with endogenous progesterone deficiency, e.g. menstrual alterations, primary or secondary infertility or premenopause. To the best of our knowledge, no pharmacogenetic studies have been published in relation to exogenous progesterone pharmacokinetic safety or progesterone metabolites so far.

Methods: Candidate-gene study where we evaluated whether five single-nucleotide polymorphisms (CYP2C9*2, *3, CYP2C19*2, *3 and *17) were related to the pharmacokinetics, safety and metabolism of progesterone in 24 healthy volunteers who received a 200-mg progesterone formulation either orally or vaginally.

Results: The vaginal formulation had an average AUCt value approximately 18 times greater than the oral formulation. CYP2C19 intermediate metabolizers (IM) consistently showed higher adjusted AUCt and adjusted C than extensive metabolizers (EM) (P < 0.05); CYP2C9 EM incongruently exhibited higher adjusted C and longer half-life than IM (p < 0.05).

Conclusion: This is the first study that reports variability in progesterone disposition according to the CYP2C19 and CYP2C9 phenotype. We suggest that CYP2C19 may condition progesterone disposition and that it may be more relevant than CYP2C9. This study lays the foundations for further in-depth research to evaluate the pharmacogenetics of progesterone.

Trial Registration: EudraCT numbers are 2012-005105-43 and 2012-005011-10.