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`ELSEVIER
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`This material may be protected by Copyright law (Title 17 US, Code)
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`Contraception 68 (2003) 421—426
`
`Original research article
`
`
`
`Contraception
`
`
`
`The pharmacokinetics of mifepristone in humans reveal insights into
`differential mechanisms of antiprogestin action
`
`Oskari Heikinheimoa’b’*, Raimo Kekkonenb’c, Pekka L'ahteenm'akib
`
`“Department of Obstetrics and Gynecology, University of Helsinki, P. 0. Box 140, SF-00029, HUS, Helsinki, Finland
`bSteroid Research Laboratory, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
`cLohja Hospital, Lohja Hospital Area, Lohja, Finland
`
`Received 24 October 2002; received in revised form 3 February 2003; accepted 17 March 2003
`
`
`
`Abstract
`
`The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half—life of 25—30 h, and high micromolar serum
`concentrations following ingestion of doses of 2100 mg of the drug. The serum transport protein—a l-acid glycoprotein (AAG)—regulates
`the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of
`distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion
`of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively
`metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4.
`The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain
`considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges
`similar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus its metabolites—seems to be responsible for the
`biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on
`optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ
`from those needed in emergency contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results in
`linear pharrnacokinetics. However, the 2200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in
`saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of
`mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2—5 mg,
`respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical
`arena. © 2003 Elsevier Science Inc. All rights reserved.
`
`Keywords: Metabolism; High performance—liquid chromatography; Radioinununoassay; Emergency contraception; Medical abortion; Dose-response
`relationships
`
`1. Introduction
`
`Recent clinical studies on the use of mifepristone in
`medical termination of pregnancy and in emergency con-
`traception 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—3]. In these studies, the
`percentages of complete abortions have ranged 88—96%
`[1—3]. The results of preliminary studies have suggested that
`
`* Corresponding author. Fax: +358-9-47l74801.
`E—mail address: oskari.heikinheimo@helsinki.fi (O. Heikinheimo).
`
`even a lOO-mg dose of mifepristone might be equally ef—
`fective [4]. However, in a randomized multicenter study
`arranged by the World Health Organization (WHO), 50 mg
`of mifepristone combined with vaginally administered pros—
`taglandin 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 effec-
`tive as 50 mg or 600 mg doses, each preventing 84—86% of
`pregnancies [6]. In fact, the lowest effective dose of mife-
`pristone in emergency contraception has not been charac—
`terized. The more than lO-fold difference in the doses of
`
`0010-7824/03/$ — see front matter © 2003 Elsevier Science Inc. All rights reserved.
`doi:10.10l6/SOOlO-7824(O3)00077—5
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`3 '
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`6-
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`4 -
`
`
`
`MIFEPRISTONE1O'6MOL/L
`
`10
`
`1
`
`0.1
`
`0.01
`0.001
`0.0001
`
`
`
`. l
`; \3
`1‘2,
`
`r'
`
`i
`
`\
`
`
`
`1
`
`23456 1
`HOURS
`
`
`
`Fig. 1. Serum levels (mean i SE) of mifepristone following administration of 2 mg (I) and 25 mg (
`both linear (lower) and semilogarithmic (upper) scales. Redrawn from Kekkonen et al. [17].
`
`HOURS
`
`DAYS
`
`
`
`
`
`) to five female volunteers. The data are depicted on
`
`mifepristone required for optimal clinical effects in emer-
`gency 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 preg—
`nan y 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 2200 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.
`
`2. Pharmacokinetics of mifepristone
`
`tabolized, 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 following ingestion of doses
`currently used in clinical practice—allowed us to develop
`methods based on HPLC for detailed analysis of the phar—
`macokinetics and metabolism of mifepristone [16]. Column
`chromatography can be used to separate the metabolites
`from the parent mifepristone, which can then be measured
`specifically either by RIA or HPLC [13].
`
`2.2. Absorption and distribution of mifepristone
`
`ingestion, mifepristone is rapidly ab—
`Following oral
`sorbed and the time to peak serum levels (tum) is approx—
`imately 1—2 h [11—13]. Also, when analyzed by specific
`RIA or HPLC, the tmax values have been similar within the
`dose range of 200—600 mg of mifepristone [16,17]. Peak
`concentrations (Cmnx) rise according to the dose of mife-
`pristone within the dose range of 2—25 mg [17]. However, at
`higher doses of 100—800 mg, Cmx values do not differ
`significantly, most likely as a result of saturation of the
`serum binding capacity for mifepristone [16]. The bioavail-
`ability has been estimated to be 40% following oral intake
`of 100 mg of mifepristone [18]. Unfortunately, attempts to
`bypass the first—pass metabolism by means of vaginal ad—
`ministration resulted in low serum levels of mifepristone
`[19].
`
`2.1. Assay systems for mifepristone
`
`2.3. Serum levels of 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—14]. It
`soon became apparent that mifepristone is extensively me—
`
`The pharmacokinetics of mifepristone have been studied
`following single oral doses ranging 2—800 mg. Following
`ingestion of 2 and 25 mg doses, the levels of mifepristone,
`as well as the areas under the concentration curves (AUCs),
`rise according to the dose (Fig. 1) [17]. However, following
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`0. Heikinheimo er al. / Contraception 68 (2003) 421—426
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`423
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`MIFEPRISTONE
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`1o-6MOL/L
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`HOURS
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`MONODEMETHYLATED METABOLITE
`«a.
`a...
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`'r
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` 1o-6MOLIL
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`HOURS
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`DIDEMETHYLATED MATABOLITE
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`HYDROXYLATED METABOLITE
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`
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`1o-6MOLIL
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`HOURS
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`HOURS
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`/
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`Fig. 2. Serum levels (mean :- SE) of mifepristone and its monodemethylated, hydroxylatcd and didemethylated metabolites following administration of single
`doses of 100, 400, 600 and 800 mg to female volunteers. Statistically significant differences in the serum levels between the groups ingesting 100 and 800
`mg are indicated by asterisks (*p < 0.05; **p < 0.01; ***p < 0.005; ****p < 0.001). Redrawn from Heikinhcimo et a1. [16].
`
`intake of single doses of 100, 400, 600 and 800 mg, the
`concentrations of mifepristone have all been observed to be
`at ~25 umol/L at 24 h (Fig. 2) [16] despite the nearly
`10-fold difference in the dose ingested.
`When administered repeatedly, a similar phenomenon in
`the plateau levels is seen when the daily dose of mifepristone
`exceeds 100 mg [20]. Figure 3 shows the individual and mean
`levels of mifepristone in a group of six women given 50 mg
`twice a day for 7 days. The individual levels of mifepristone
`were similar among the subjects, and the individual half-lives
`of mifepristone varied from 26—48 h. The micromolar serum
`concentrations of mifepristone also persist during prolonged
`daily treatment with 200 mg for up to 20 months [21].
`
`2.4. Serum binding characteristics of mifepristone
`
`In human serum, 94 —99% of mifepristone is protein
`bound [10,16]. Early studies by Moguilewsky and Philibert
`[22] indicated that human serum, unlike rat serum, contains
`a high—affinity binding protein for mifepristone, which was
`soon identified as a l—acid glycoprotein (AAG). The highly
`
`significant correlations between serum levels of mifepris—
`tone and AAG suggested that AAG has a great impact on
`the pharmacokinetics of mifepristone in man [16,23]. Stud-
`ies involving centrifugal ultrafiltration dialysis showed that
`a serum concentration of mifepristone of 2.5 umol/L rep-
`resents saturation of AAG binding capacity (Fig. 4) [16]. In
`addition, albumin appears to have a high-capacity role in the
`serum transport of mifepristone [16].
`Thus, in humans, serum AAG appears to limit the tissue
`availability of mifepristone. However, mifepristone exceed—
`ing the binding capacity of AAG may be more susceptible
`to excretion or possibly diffusion into peripheral tissues
`[24]. In accordance with the low volume of distribution,
`tissue mifepristone levels have been observed to be in the
`same range or lower than serum levels following intake of
`200 mg of mifepristone prior to hysterectomy [24].
`
`2.5. Metabolism of mifepristone in humans
`
`The elimination phase half—life of mifepristone (t I ,2) has
`been reported to vary between 24 and 48 h when analyzed
`
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`MIFEPHlSTONE 50 MG b.i.d. x 7d.
`
`10—I _
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`5 6 m
`
`ean + SEM
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`10'6MOL/L
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`
`
`0.01i—l—l—i—v—r—r—i—_I—V—1
`12
`14
`16
`18
`20
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`DAYS
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`Fig. 3. Individual and mean (:L'SE) levels of mifepristone during intake of 50 mg twice a day for 7 days in six female volunteers. Redrawn from Heikinheimo
`[20].
`
`by HBLC [14,20]. However, investigators employing either
`RIArbr RRA have reported t1,2 values between 54 and 90 h
`[11,25], this most likely a result of the presence of cross—
`reacting metabolites of mifepristone.
`The metabolism of mifepristone is initiated by rapid
`demethylation and hydroxylation in humans, rats and mon-
`keys [18]. The enzyme CYP3A4 has been shown to be the
`primary cytochrome P-450 enzyme responsible for the ox-
`idative metabolism of mifepristone in human liver micro—
`somes [26]. Following oral
`intake of 100 mg or more,
`constant serum levels of mifepristone, but increasing con-
`centrations of the monodemethylated, didemethylated and
`
`501
`
`”fl”— HUMAN SERUM
`
`46- + AAG-SOLUTION (0.19/1)
`"El-’- ALBUMlN-SOLUTION (459")
`
`NON-PROTElN-BOUND(3H)—MlFEPRISTONE
`
`
`CONCENTRATION OF MIFEPRISTONE (x10 ' 6 M)
`
`Fig. 4. Percentage of serum non-protein—bound mifepristone (mean : SE)
`in human serum, in phosphate—buffered saline (PBS) containing human
`alpha l—acid glycoprotein (AAG), and in PBS containing human albumin.
`Redrawn from Heikinheimo et al. [16].
`
`hydroxylated metabolites of mifepristone are found, with
`serum levels of the monodemethylated metabolite exceed-
`ing those of the parent compound [16,27]. Following ad-
`ministration of mifepristone at doses over 400 mg,
`the
`concentrations of the didemethylated and hydroxylated me-
`tabolites also exceed those of the parent compound (Fig. 2)
`[16]. Peak levels of the monodemethylated and hydroxy-
`lated metabolites are reached by 2—4 h. The time course of
`the didemethylated metabolite is somewhat different, with
`peak levels being measured only after 10 h following in—
`gestion of mifepristone.
`The demethylated and hydroxylated metabolites are fur-
`ther metabolized and excreted into bile. In humans, only a
`
`very small fraction of mifepristone can be detected in urine
`[18].
`
`3. Binding of mifepristone and its metabolites to hPR
`and hGR
`
`Tables 1 and 2 summarize the relative binding affinities
`(RBAs) of mifepristone, the monodemethylated, hydroxy-
`lated and didemethylated metabolites, as well as those of
`reference steroids,
`to the human progesterone receptor
`(hPR) and glucocorticoid receptor (hGR) [15]. The rela—
`tively high receptor-binding affinities of mifepristone’s me-
`tabolites 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 parent com—
`pound as well as the pool of metabolites.
`The efficacy of mifepristone in pregnancy termination
`
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`425
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`Table 1
`
`Relative binding affinities (RBAs) of mifepristone and its three
`metabolites to the human uterine progesterone receptor
`
`
`
` Compound RBA %
`
`374
`ORG-2058
`100
`Mifepristone
`43
`Progesterone
`21
`Monodemethylated metabolite
`15
`Hydroxylated metabolite
`
`Didemethylated metabolite 9
`
`cannot be improved by increasing the dose beyond 200 mg
`[1—3]. Thus, based on the similar serum concentrations of
`
`mifepristone, but increasing levels of the metabolites fol-
`lowing intake of 2100 mg of mifepristone (Fig. 2), it may
`be speculated that the lower affinities of the metabolites
`
`towards hPR (Table 1) imply minor importance of these
`metabolites in the abortifacient action of mifepristone.
`In comparison with hPR, the RBAs of the monodem—
`ethylated, hydroxylated and didemethylated metabolites to-
`ward hGR (Table 2) are more pronounced. The antiglu—
`cocorticoid effects of mifepristone increase in a dose-
`dependent manner following ingestion of doses of 2200 mg
`[7,8]. Thus, based on the similar serum levels of parent
`mifepristone but increasing levels of the metabolites, it may
`be speculated that
`the metabolites are important in the
`antiglucocorticoid actions of mifepristone.
`
`4. 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 ZOO-mg dose, but not a 50-mg dose, of
`mifepristone in combination with prostaglandin is effective
`in pregnancy termination [1—3,5]. In fact, even a lOO-mg
`dose of mifepristone might be acceptably effective [4]. In
`view of the saturation stage pharmacokinetics of mifepris-
`tone following intake of doses of 100 mg and more, the
`efficacy of the 100 mg dose is not surprising. Thus, for
`termination of pregnancy, the saturation stage serum kinet—
`ics of mifepristone appear important. It may be speculated
`
`Table 2
`
`Relative binding affinities (RBAs) of mifepristone and its three
`metabolites to the human placental glucocorticoid receptor
`
` Compound
`
`RBA %
`
`100
`Mifepristone
`61
`Monodemethylated metabolite
`48
`Hydroxylated metabolite
`45
`Didemethylated metabolite
`23
`Dexamathasone
`
`Cortisol 9
`
`in-
`the abortifacient properties—decidual bleeding,
`that
`creased uterine contractility and sensitivity to prostaglan—
`dins—require complete saturation of the uterine progester—
`one receptors.
`
`When women with complete and incomplete termination
`of pregnancy following administration of a single dose of
`600 mg of mifepristone were compared, the serum levels of
`mifepristone and those of the three metabolites were indis-
`tinguishable [28]. It therefore appears that individual uterine
`sensitivity to progesterone withdrawal, and not differences
`in the pharmacokinetics of mifepristone, dictate the even-
`tual clinical outcome of each subject.
`In emergency contraception, mifepristone doses in the
`range of 10—600 mg behave similarly, inhibiting 84—85% of
`pregnancies [6]. Therefore, the mechanism by which mifepris-
`tone acts as an emergency contraceptive is clearly different
`from its ability to start a cascade resulting in termination of
`pregnancy. Continuous daily administration of 2 mg of mife-
`pristone or more inhibits ovulation in women [29,30]; this
`inhibition occurs most likely via central mechanisms [29,30].
`As inhibition or delay of ovulation also appears to be a major
`mechanism of action in emergency contraception [31], 10 mg
`of mifepristone, and thus linear range serum levels of the drug,
`are sufficient for the presumed ovulation inhibition. It may be
`speculated that an even lower dose than 10 mg of mifepristone
`might be effective in emergency contraception. As the endo-
`metn'um appears to be very sensitive to the effects of mife—
`pristone [32,33], possible actions on the endometrium might
`complement the efficacy of mifepristone in emergency contra—
`ception.
`/.-’/
`Mifepristone has several pharmacokinetic features that
`make it very useful in both termination of pregnancy and in
`emergency contraception. It is rapidly absorbed and the
`bioavailability of mifepristone is sufficient for clinical use.
`The long t1,2 of mifepristone allows effective single—dose
`treatment, and thus controlled distribution for both clinical
`
`indications. It may be argued that identification of the min-
`imal effective dose, which may be approximately 100 mg
`for pregnancy termination and 2—5 mg for emergency con-
`traception, is important. It remains to be seen whether some
`of the newly synthesized antiprogestins with higher selec—
`tivity will be clinically superior to mifepristone.
`
`Acknowledgments
`
`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 Foun—
`dation Clinical Fellowship grant.
`
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`6
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`

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