Original research articleThe pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action
Introduction
Recent clinical studies on the use of mifepristone in medical termination of pregnancy and in emergency contraception have focused on optimization of mifepristone regimens. In termination of first-trimester pregnancy, a 200-mg dose of mifepristone, in combination with vaginally administered prostaglandin, is equally effective as a higher dose (600 mg) of mifepristone [1], [2], [3]. In these studies, the percentages of complete abortions have ranged 88–96% [1], [2], [3]. The results of preliminary studies have suggested that even a 100-mg dose of mifepristone might be equally effective [4]. However, in a randomized multicenter study arranged by the World Health Organization (WHO), 50 mg of mifepristone combined with vaginally administered prostaglandin was 1.6 times more likely to fail in termination of first trimester pregnancy when compared with a regimen containing 200 mg of mifepristone [5].
In emergency contraception, considerably lower doses of mifepristone are needed. In a randomized study arranged by the WHO, a 10-mg dose of mifepristone was equally effective as 50 mg or 600 mg doses, each preventing 84–86% of pregnancies [6]. In fact, the lowest effective dose of mifepristone in emergency contraception has not been characterized. The more than 10-fold difference in the doses of mifepristone required for optimal clinical effects in emergency contraception and in pregnancy termination suggests that different biological mechanisms mediate these clinical effects of mifepristone.
The antiglucocorticoid effects of mifepristone are in sharp contrast with its antiprogestagenic effects in pregnancy termination or in emergency contraception. Early studies by Bertagna et al. [7] and Gaillard et al. [8] showed that activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to mifepristone is clearly a dose-dependent phenomenon, and significant increases in the circulating concentrations of adrenocorticotropic hormone and cortisol are seen following administration of ≥200 mg of the drug. Moreover, more pronounced activation of the HPA axis is seen as the dose of mifepristone is increased [7], [8].
The differences in the clinical effects of mifepristone are also related to its pharmacokinetics—the high efficacy of mifepristone in emergency contraception is seen in the dose range that results in linear kinetics of the drug in serum. However, the doses required for termination of pregnancy or activation of the HPA axis result in saturation level, non linear kinetics of mifepristone. In this article we review the pharmacokinetics of mifepristone in humans, with special emphasis on the relationships between its pharmacokinetics and clinical efficacy.
Section snippets
Assay systems for mifepristone
Various assay methods such as radioimmunoassay (RIA) [9], radioreceptorassay (RRA) [10], [11] and assays based on high-performance liquid chromatography (HPLC) have been used to measure serum mifepristone levels [12], [13], [14]. It soon became apparent that mifepristone is extensively metabolized, and due to the cross-reacting metabolites, direct RIA and RRA failed to distinguish the parent mifepristone from its metabolites [15]. However, the micromolar serum levels of mifepristone—seen
Binding of mifepristone and its metabolites to hPR and hGR
Table 1, Table 2 summarize the relative binding affinities (RBAs) of mifepristone, the monodemethylated, hydroxylated and didemethylated metabolites, as well as those of reference steroids, to the human progesterone receptor (hPR) and glucocorticoid receptor (hGR) [15]. The relatively high receptor-binding affinities of mifepristone’s metabolites in combination with the high serum levels of the metabolites suggest that some of the biological effects of mifepristone may be mediated via both the
Pharmacokinetics vs. clinical effects of mifepristone
Understanding the pharmacokinetics of mifepristone has aided the design of studies aimed at optimizing mifepristone regimens. In several randomized multicenter studies, it has become clear that a 200-mg dose, but not a 50-mg dose, of mifepristone in combination with prostaglandin is effective in pregnancy termination [1], [2], [3], [5]. In fact, even a 100-mg dose of mifepristone might be acceptably effective [4]. In view of the saturation stage pharmacokinetics of mifepristone following intake
Acknowledgements
Our studies have been carried out with financial support from The Population Council (New York City, NY, USA). Dr. Heikinheimo is a recipient of a Finnish Medical Foundation Clinical Fellowship grant.
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