Clinical pharmacokinetics of mifepristone

Clin Pharmacokinet. 1997 Jul;33(1):7-17. doi: 10.2165/00003088-199733010-00002.

Abstract

Mifepristone is a steroidal antiprogestin and antiglucocorticoid acting at the receptor level. The aromatic dimethylaminophenyl side chain in position 11 of the steroid structure is essential for the antagonistic properties of mifepristone. The pharmacokinetics of mifepristone are characterised by rapid absorption, a long half-life of 25 to 30 hours and micromolar serum concentrations following ingestion of doses currently in clinical use. The serum transport protein alpha 1-acid glycoprotein (AAG) regulates the serum kinetics of mifepristone. Binding to AAG limits the tissue availability of mifepristone, explaining the low metabolic clearance rate of 0.55 L/kg/day and the low volume of distribution of mifepristone. Also, similar serum concentrations of mifepristone following ingestion of single doses exceeding 100mg can be explained by saturation of the binding capacity of serum AAG. Following oral intake, mifepristone is extensively metabolised by demethylation and hydroxylation, the initial metabolic steps are catalysed by the cytochrome P450 (CYP) enzyme CYP3A4. The 3 most proximal metabolites, namely the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward the human progesterone and glucocorticoid receptors; in addition, the serum concentrations of these 3 metabolites are in a similar range as those of the parent drug. Thus, the combined pool of mifepristone, as well as that of the metabolites, seems responsible for the biological actions of mifepristone. Combination therapy with mifepristone and low dose prostaglandin is currently in clinical use for termination of early pregnancy in China, France, Sweden and the UK. The combined regimen is well tolerated and highly efficacious with a 95% rate of complete pregnancy terminations. Recent clinical studies on pregnancy termination have focused on dose optimisation of mifepristone and evaluation of the orally active prostaglandin derivative misoprostol. In addition, several other indications for the clinical use of mifepristone, such as induction of labour, contraception, as well as treatment of various hormone dependent disorders, are emerging. The major obstacles currently inhibiting further evaluation and distribution of mifepristone are political rather than clinical. However, it is hoped that the eventual introduction of new antiprogesterone molecules by several manufacturers will enhance the availability of this important class of new drugs.

MeSH terms

  • Abortifacient Agents, Steroidal* / pharmacokinetics
  • Abortifacient Agents, Steroidal* / pharmacology
  • Abortifacient Agents, Steroidal* / therapeutic use
  • Abortion, Induced
  • Breast Neoplasms / drug therapy
  • Contraception
  • Endometriosis / drug therapy
  • Female
  • Humans
  • Labor, Induced
  • Leiomyoma / drug therapy
  • Meningioma / drug therapy
  • Mifepristone* / pharmacokinetics
  • Mifepristone* / pharmacology
  • Mifepristone* / therapeutic use
  • Pregnancy
  • Progestins / antagonists & inhibitors

Substances

  • Abortifacient Agents, Steroidal
  • Progestins
  • Mifepristone