Pharmacokinetics
`Low Oral Doses
`
`of Mifepristone After
`
`ELSEWER
`
`Raimo Kekkonen, Oskari Heikinheimo,
`
`Erik Mandelin and Pekka Lahteenmgki
`
`(RU
`mifepristone
`low doses of the antiprogestin
`Relatively
`for a variety
`of
`recently
`proven
`to be efficient
`486) have
`the pharmaco-
`possible
`clinical
`uses of the drug. However,
`kinetics
`after
`low single
`oral doses have not been charac-
`terized. We evaluated
`the pharmacokinetics
`of mifepris-
`tone
`following
`single
`ingestion
`of 2 and 25 mg
`in
`five
`of 8 mg
`women
`as well
`as repeated
`ingestion
`in
`two
`women. Maximal
`serum
`concentrations
`were
`reached
`rap-
`idly
`(within
`0.5-2 h) with
`all doses used. Serum mifepris-
`tone
`concentrations
`were proportional
`to
`the oral doses
`taken.
`The mean
`(*SD)
`areas under
`the concentration
`curves
`(AU&)
`(O-24 h) were 1134
`(*144), 4846
`(*64), and
`17,015
`(*4,421)
`h x nglmL
`following
`2, 8, and 25 mg doses,
`respectively.
`No cumulative
`increases
`in serum
`concentra-
`of
`tions were detected with prolonged
`daily administration
`8 mg of mifepristone.
`The study subjects
`appeared
`to vary
`in
`their ability
`to metabolize
`mifepristone,
`as two different
`half-lives
`(tI,,) emerged
`after both 2 and 25 mg single doses
`(24.2 * 0.6 [SD] h for three subjects;
`and 44.4 * 1.8 [SD] h
`for two subjects). We conclude that within the dose range
`of 2-25 mglday,
`the pharmacokinetics
`of mifepristone
`are
`linear,
`unlike
`those seen following
`ingestion
`of higher
`daily
`doses. Keeping
`in mind
`previously
`published
`data on
`the
`biological effects
`low dose mifepristone administration,
`of
`these data
`infer
`that
`certain
`effects of the drug,
`such as
`inhibition
`of ovulation,
`might
`be achieved
`at serum
`con-
`0 1996 Elsevier
`centrations
`of approximately
`100 ng/mL.
`Science Inc. All rights reserved. CONTRACEPTION
`1996;54:
`229-234
`
`antiprogestin RU 486, single dose, multiple
`KEY WORDS:
`doses, radioimmunoassay,
`individual
`variability
`
`Introduction
`in
`using mifepristone
`termination
`regnancy
`with a prostaglandin
`is the only
`combination
`I?
`accepted purpose
`for the clinical
`use of mifepris-
`tone. When used
`for pregnancy
`termination,
`single
`doses of mifepristone
`have
`ranged
`from 200-600
`mg. if2 Hence
`the pharmacokinetics
`of mifepristone
`have mainly
`been examined
`in connection with
`these
`relatively
`large doses.
`sen-
`Different
`target organs appear to have different
`sitivities
`to mifepristone.
`High single doses, 400 mg
`or more, are needed
`to induce an increase
`in ACTH
`secretion. Similarly,
`400 mg of mifepristone
`is needed
`to overcome
`the suppressive effect of 1 mg dexameth-
`asone
`(DXM) on ACTH
`and cortisol
`secretion3
`and
`600 mg of the drug is needed
`to overcome
`the clinical
`symptoms
`of hypercortisolemia.4
`Inhibition
`of ovula-
`tion has been achieved with daily
`repeated doses of
`2-25 mg of RU 486,5-8 but not in all studies has a dose
`of 2 mg been sufficient.’
`However, when given
`just
`prior
`to ovulation,
`as little
`as 1 mg of the drug
`is
`inhibitory.i’,”
`Thus,
`the threshold
`to disturb
`the hy-
`pothalamic-pituitary-ovarian-axis
`(HPO-axis)
`in hu-
`mans appears
`to be about 2 mg.6f7t10,11 Similarly,
`re-
`gression of uterine
`leiomyomata
`has been shown
`to
`occur
`in a dose-dependent manner, daily administra-
`tion of 25 or 50 mg being significantly
`more effective
`than 5 mg. l2 Endometrial
`changes which might
`result
`in disturbances
`of implantation
`of fertilized
`ova have
`been achieved
`at both moderate
`(50 mg/day)13
`and
`low (1 mg/day)14
`repetitive
`doses of the drug. Mife-
`pristone
`is perhaps
`the most promising
`candidate
`for
`effective emergency
`contraception.‘5,‘6
`However,
`the
`optimal
`dose for this
`indication
`remains
`to be deter-
`mined.
`of low-
`possibilities
`In view of the various clinical
`dose mifepristone
`therapy,
`especially
`its potential
`contraceptive
`uses, the purpose of this study was to
`examine
`the pharmacokinetics
`of relatively
`low doses
`of mifepristone
`in women. Our hypothesis was that
`the doses used in
`this study
`(2, 8, and 25 mg) would
`produce
`linear,
`dose-dependent
`serum mifepristone
`concentrations.
`
`of
`
`Re-
`P.O.
`Tel:
`
`Chemistry,
`
`Institute
`
`of Medical
`Department
`Laboratory,
`Research
`Steroid
`Finland
`Biomedicine,
`University
`of Helsinki,
`Helsinki,
`Steroid
`Lahteenmaki.
`Dr. Pekka
`Name
`and address
`for correspondence:
`search
`Laboratory
`Department
`of Biochemistry,
`Institute
`of Biomedicine,
`Box
`8 (Siltavuorenpenger
`lo),
`FIN-00014
`University
`of Helsinki,
`Finland.
`(358-O)
`1918235;
`Fax:
`(358-O)
`1918276
`Submitted
`for publication
`March
`5, 1996
`Revised
`June
`24, 1996
`Accepted
`for publication
`
`July
`
`12, 1996
`
`Elsevier
`0 1996
`655 Avenue
`of
`
`reserved.
`rights
`Inc. All
`Science
`the Americas,
`New York, NY 10010
`
`ISSN OOlO-7824/96/$15.00
`PII SOOIO-7824(96)00193-X
`
`

`

`230 Kekkonen
`
`et al
`
`Contraception
`1996;54:229-234
`
`Materials and Methods
`Subjects
`clinic of
`at the outpatient
`The study was performed
`City of Lohja, Finland. The
`Lohja District Hospital,
`study protocol
`and human
`experimentation
`were ap-
`proved by the ethics committee
`of the hospital.
`Five
`healthy women
`(subjects
`l-5), aged between 29 and
`37 years, volunteered
`for the two stages of the single-
`dose study
`(2 and 25 mg).
`Informed
`consent was ob-
`tained prior
`to initiation
`of the study. The subjects
`did not use hormonal
`contraception
`or any other hor-
`monal
`therapy
`for
`the
`three months
`preceding
`the
`study or during
`it. The
`two subjects
`(subjects 6 and 7)
`undergoing
`daily administration
`of 8 mg
`for 30 days
`were part of a previous
`study
`in which we evaluated
`ovulation
`inhibition
`after
`low-dose mifepristone
`ad-
`ministration.*
`We now report
`the pharmacokinetics
`of mifepristone,
`evaluated
`from
`the same samples.
`
`Medication
`p-14-
`486; 17P-hydroxy-l l
`(RU
`Mifepristone
`17a-[ 1 -propynyl]-estra-4,9-
`dimethylamino-phenyll-
`as 200 mg
`tablets
`from
`dien-3-one)
`was obtained
`France) and as 50 mg tab-
`Roussel-Uclaf
`(Romainville,
`Council
`(New York City,
`lets
`from
`the Population
`by Roussel-Uclaf].
`The 200
`NY]
`(also manufactured
`into 2 mg capsules at
`the
`mg
`tablets were divided
`Pharmacy
`of the University
`of Helsinki,
`Helsinki,
`(2
`Finland. Subjects 1-5 received a single oral capsule
`mg) of mifepristone
`in
`the morning
`of one of cycle
`days
`l-7.
`In the next menstrual
`cycle,
`they
`received
`half of a 50-mg
`tablet
`(25 mg) by the same route. Sub-
`
`four capsules of 2 mg of mife-
`jects 6 and 7 received
`pristone
`(8 mg) daily
`for 30 days, starting
`in the morn-
`ing of day 1 of the study. Thereafter,
`the capsules
`were ingested
`in the evenings.8
`
`Assays
`and Hormone
`Sample Collection
`Venous blood samples were collected
`from subjects
`l-5 before mifepristone
`administration
`(O-sample)
`7
`and at l/2, 1, 2, 4, 6, 24, and 36 h, then daily until
`days after
`ingestion.
`From
`subjects
`6 and 7, the
`samples were obtained
`in
`the same way for the first
`24 h. Samples were then collected
`daily
`for the first
`week of mifepristone
`treatment,
`and thereafter
`three
`times a week until
`the next menstrual
`period, which
`occurred 19 days following
`termination
`of the treat-
`ment
`in both subjects.’ Serum was separated by cen-
`trifugation
`and the samples were stored at -20°C un-
`til assayed.
`were de-
`of serum mifepristone
`The concentrations
`(RIA)
`fol-
`radioimmunoassay
`termined
`by a specific
`lowing Chromosorb-column
`chromatography.”
`The
`practical
`detection
`limit
`of the RIA was 0.61 ng/mL.
`The mean
`intra- and interassay
`coefficients
`of varia-
`tion
`(CV) of the RIA were 9.3% and 12.7%,
`respec-
`tively.
`To convert metric values (ng/mL)
`(nmol/l),
`the serum
`concentrations
`are multiplied
`by 2.30.
`
`into molar values
`of mifepristone
`
`Parameters
`Pharmacokinetic
`curves of serum mife-
`Areas under
`the concentration
`pristone during
`the first 24 h after drug ingestion
`
`s
`
`0123456
`
`1
`
`234567
`
`HOURS
`
`DAYS
`
`o-kT,T,T
`0123456
`
`HOURS
`
`~-Q”..l.l.,
`v,
`1
`
`2
`
`. . . . . . . . . . . . . .
`4
`
`7
`3
`
`5
`
`6
`
`I
`7
`
`DAYS
`
`1. Mean serum concentrations of mifepristone (ng/mL) in study subjects 1-5 over the first 6 h and the first 7 days
`Figure
`after single oral doses of 2 mg (solid squares) and 25 mg (open squares) of the drug. The data are depicted on both linear
`(lower) and semilogarithmic (upper) scales.
`
`

`

`Contraception
`1996;54:229-234
`
`Pharmacokinetics
`
`of Mifepristone
`
`231
`
`RU 466
`
`6 oo-
`
`500 -
`
`400 -
`
`300 -
`
`200 -
`
`‘+-m-n-~
`0123456
`
`24
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`HOURS
`
`DAYS
`
`2. Serum mifepristone concentrations (ng/mL) in
`Figure
`ingested 8 mg mifepristone orally once a day for 30 days.
`
`subjects 6 (solid squares) and 7 (open squares). The subjects
`
`for each subject using
`1 were determined
`( AU&-,a
`of elimination
`half-
`rule. l8 Estimation
`the trapezoidal
`life ( tl,,) of serum mifepristone
`was determined
`using
`the method
`of residuals.
`l9 The highest
`concentration
`detected
`in each subject after different doses was de-
`fined as the maximal
`serum
`concentration
`(C,,,).
`Times
`from drug ingestion
`until C,,
`(t,,) were reg-
`istered.
`
`Results
`(ng/mL; means +
`concentrations
`Serum mifepristone
`SD) in subjects 1-5 after single doses of 2 mg and 25
`mg are shown
`in Figure 1; both
`linear and semiloga-
`rithmic
`scales are shown. Figure 2 shows the concen-
`trations
`of mifepristone
`in subjects 6 and 7 during
`daily oral repetitive
`administration
`of 8 mg. In Table
`I the pharmacokinetic
`parameters
`of study subjects
`l-5 are shown after 2 and 25 mg single oral doses.
`Table 2 shows
`the mean
`(*SD)
`tr,,, C,,,,
`t,,,,
`and
`values
`for all doses ingested.
`Au&-m
`ranged
`(C,,,)
`Peak concentrations
`of mifepristone
`between 104 and 227 ng/mL
`after a 2-mg single dose
`of mifepristone,
`between 474 and 561 ng/mL after the
`first 8 mg dose, and between
`1285 and 4851 ng/mL
`after a 25-mg
`single dose. Peak
`concentrations
`of
`mifepristone
`were rapidly
`reached
`following
`all doses.
`The semilogarithmic
`scale (Figure 1) clearly shows
`that although
`the serum
`concentrations
`differed by
`roughly an order of magnitude,
`the rate of metabolism
`was similar
`following
`the two single doses of 2 and 25
`observed
`following
`ingestion
`of 25 mg
`mg. The C,,,
`of mifepristone
`was I8.6-fold
`higher
`than
`that after 2
`mg
`(Table 2). However,
`there was only a 12.5fold
`difference
`in
`the
`two doses. The decreases
`in serum
`mifepristone
`concentrations
`from C,,, were more
`
`than after 8 and 2 mg single
`after 25 mg
`prominent
`oral doses of mifepristone.
`The mean C,,
`values
`compared with
`the mean mifepristone
`concentrations
`after 4 h of ingestion
`(C,,:C4h)
`were 3.75 (25 mg),
`1.99 (8 mg), and 2.34 (2 mg).
`The mean
`tr,, values were 32.7 h (2 mg) and 32.0 h
`(25 mg). However,
`two different
`tr,, values were found
`(Table 1). Subjects 3 and 4 showed
`longer half-lives
`after both 2 mg and 25 mg doses, ranging between
`41.7 and 45.5 h. Subjects
`1, 2, and 5 had half-lives
`between 23.8 and 25.0 h. Linear correlation
`between
`the tl,, values
`following
`the 2 mg and 25 mg doses was
`highly
`significant
`(r = 0.99; p = 0.001). This
`indicates
`that each subject metabolized
`mifepristone
`at an in-
`dividual
`rate irrespective
`of the dose ingested.
`After beginning
`the
`treatments,
`daily administra-
`tion of 8 mg of mifepristone
`resulted
`in serum steady-
`state concentrations
`in
`two days. These concentra-
`tions
`ranged between 188 and 596 ng/mL,
`the mean
`(*SD) being 308
`(+_82) ng/mL. No cumulatively
`in-
`
`1. Pharmacokinetic parameters in subjects l-5 for
`Table
`both single oral doses of mifepristone (RU 486): 2 and 25 mg
`
`C max
`t nlax
`fl/Z
`Subject 2 mg 25 mg 2 mg 25 mg 2 mg 25 mg
`
`1
`2
`3
`4
`5
`
`25.0
`23.8
`45.5
`45.5
`23.8
`
`23.8
`25.0
`41.7
`45.0
`23.8
`
`104
`183
`227
`121
`142
`
`1285
`2361
`4851
`1967
`3958
`
`2
`0.5
`0.5
`2
`2
`
`1
`1
`1
`2
`2
`
`= time
`t,,
`(ng/mLJ;
`concentration
`serum
`= maximal
`(hJ; C,,,
`t,,, = half-life
`metric
`(h). To convert
`concentration
`serum
`ingestion
`to maximal
`from
`drug
`of mife-
`concentration
`the serum
`(nmol/l),
`values
`(ng/mL)
`into molar
`values
`the
`tIi2
`coefficient
`between
`The
`correiation
`pristone
`is multiplied
`by 2.30.
`values
`following
`the 2 and 25 mg doses
`in
`the study
`subjects
`was statistically
`significant;
`r = 0.99
`(p = 0.001).
`
`

`

`232 Kekkonen
`
`et al.
`
`Contraception
`1996;54:229-234
`
`Table
`to Lax
`
`2. The mean (AD) half-lives (t,,z; h), maximal
`Itmaxj h)
`
`serum concentrations
`
`(Cmaxj ng/mL), and times from drug ingestion
`
`t1/2
`C max
`
`kzO-24h
`
`2 mg
`
`32.7 (i11.7)
`155 (+49)
`1.4 (+0.8)
`1134.4
`(d43.9)
`
`8 mg
`
`n.a.
`518 (i62)
`1.5 (kO.7)
`4846.0
`(+63.7)
`
`25 mg
`
`32.0 (k10.7)
`2884
`(A474)
`1.4 (+0.5)
`17015.2
`(k4421.0)
`
`The mean
`ingestion;
`
`(*SD)
`subjects
`
`areas
`l-5
`
`under
`ingested
`
`the
`
`[AUC;
`curve
`2 and 25 mg
`
`h x ng/mL)
`(n = 5), subjects
`
`calculated
`were
`6 and
`7 ingested
`
`mifepristone
`serum
`from
`8 mg (n = 2).
`
`concentrations
`
`in each
`
`subject
`
`between
`
`O-24
`
`h after
`
`were seen during multiple
`concentrations
`creasing
`doses of the drug (Figure 2).
`The clinical
`results
`from subjects 6 and 7 are re-
`ported elsewhere.8
`
`in
`
`Discussion
`(RU 486)
`of mifepristone
`The pharmacokinetics
`humans
`are characterized
`by extensive metabolism,
`a long half-life
`of approximately
`25 h, and non-lin-
`earity
`following
`ingestion
`of 50 mg or more of the
`drug. 17~20-23 The non-linear
`pharmacokinetics
`have
`been explained
`in part by saturation
`of the specific
`serum
`transport
`protein
`for mifepristone,
`serum al-
`pha-l-acid
`glycoprotein
`(AAG)(orosomucoid).24
`AAG
`has been shown
`to become saturated at a serum con-
`centration
`of approximately
`2500 nmol
`(1100 ng/mL)
`of mifepristone/L.
`20~25 Thus, after single dose admin-
`istration
`of 100 mg or more, serum concentrations
`of
`mifepristone
`do not rise in accordance
`to the dose.17r2’
`In the present study, more
`than a tenfold difference
`was seen in serum concentrations
`following
`ingestion
`of 2 mg and 2.5 mg of mifepristone.
`This
`is consistent
`with previous data regarding
`the saturation
`of AAG
`Serum
`concentrations
`of mife-
`by mifepristone.20125
`pristone
`(AUCO-24h) were proportional
`the oral
`doses of 2, 8, and 25 mg.
`tl,, of
`the
`In
`the single-dose
`results of this study,
`mifepristone
`was similar
`in
`individual
`subjects
`fol-
`lowing both 2 mg and 25 mg doses. Thus, each indi-
`vidual appeared
`to metabolize mifepristone
`similarly
`following
`both doses. The correlation
`coefficient
`be-
`tween
`the two tl,, values was highly
`significant.
`The
`study subjects appeared
`to vary in their ability
`to me-
`tabolize mifepristone.
`Individual
`differences
`in mife-
`pristone metabolism
`have also been demonstrated
`in
`dogs.26 Studies with
`the hepatic
`cytochrome
`P-450
`superfamily
`have revealed
`that P-450
`IIIA
`is involved,
`inter alia,
`in mifepristone
`and estrogen metabolism,
`and P-450
`IIC,
`i.a.,
`in progesterone metabolism.
`Ge-
`netic polymorphism
`as it relates
`to the cytochrome
`in
`P-450 system,
`is suggested
`to be a primary
`factor
`interindividual
`differences
`in drug metabolism
`with a
`
`to
`
`great variety of drugs. 27~28 The results of the present
`study do not, however, allow us to compare details of
`the metabolic
`pathways of mifepristone
`between sub-
`jects.
`has
`of 25 mg of mifepristone
`Daily administration
`con-
`to bring about steady-state
`been demonstrated
`centrations
`of approximately
`400 ng/mL,29 and with
`50 mg doses, approximately
`1100 ng/mL.25 Recently,
`using a different assay system
`for mifepristone,
`Crox-
`atto and co-workers
`reported steady-state
`levels of ap-
`proximately
`35 ng/mL
`after 1 mg daily doses, 175
`ng/mL
`after 5 mg, and 350 ng/mL
`after 10 mg daily
`prolonged
`administration
`of mifepristone.’
`The
`re-
`sults of the present study support
`the results of these
`earlier
`studies;
`continuous
`daily administration
`of
`mifepristone
`does not result
`in cumulative
`increases
`in serum
`drug concentrations.
`Steady-state
`levels
`with
`the dose of 8 mg were approximately
`3 10 rig/ml,
`which
`is also in line when compared with
`the results
`of these other studies.
`their
`reached
`concentrations
`Serum mifepristone
`.4 h after all
`maxima
`rapidly,
`in approximately
`1.2-l
`the doses studied. This
`is in agreement with
`the re-
`sults of studies
`in which,
`for the most part, higher
`doses of the drug were used. 1’,20,21,23,25,30,31 1n earlier
`studies with single oral doses, C,,,
`values were not
`linearly
`dose-dependent.
`In
`the redistribution
`phase,
`the concentrations
`reached a plateau
`at a level of
`about 1100 ng/mL. These plateau
`concentrations
`did
`not rise in a dose-dependent manner after administra-
`tion of more
`than 100 mg
`in single doses.17t20,21,23 In
`the present study,
`linearly
`increasing mean C,,
`val-
`ues were measured
`following
`2, 8, and 25 mg of mife-
`pristone. Furthermore,
`although
`the C,,, with
`the 25
`mg dose rose above 1100 ng/mL, no clear plateau was
`seen with any of the doses used. This
`is in agreement
`with
`the concept
`that AAG will not be fully saturated
`after a single dose of 25 mg of mifepristone.
`of mife-
`In conclusion,
`peak serum concentrations
`pristone are rapidly achieved
`in 1.2-l
`.4 h. Serum con-
`centrations
`of mifepristone
`were proportional
`to the
`oral doses of 2, 8, and 25 mg. This
`in consistent with
`previous
`data
`regarding
`the saturation
`of AAG by
`
`

`

`Contraception
`1996;54:229-234
`
`Pharmacokinetics
`
`of Mifepristone
`
`233
`
`to be interindividual
`2of25 There appears
`mifepristone.
`in
`the elimination
`of mifepristone,
`even
`differences
`with
`low single oral doses.
`
`Acknowledgments
`staff of the
`The
`invaluable
`assistance of the technical
`Tevilin,
`Steroid Research Laboratory
`(Ms. Marjatta
`Ms. Sirpa Ranta, and Ms. Eeva Harju)
`is gratefully
`acknowledged.
`This study was financially
`supported
`by the John Noble Foundation,
`the Educational
`Foun-
`dation of America,
`the George J. Hecht Fund,
`the An-
`drew W. Mellon
`Foundation,
`and
`the Rockefeller
`Foundation
`through
`the Population
`Council,
`Inc.,
`New York, NY. Financial
`support was also provided
`by the Finnish Obstetric
`and Gynecological
`Research
`Foundation
`(to RX.). The contents
`of this
`report do
`not necessarily
`reflect
`the policy of any of the funding
`sources.
`
`References
`termination
`Pregnancy
`Organization.
`1.
`World
`Health
`a multicen-
`(RU 486) and gemeprost:
`with mifepristone
`between
`repeated
`doses and a single
`tre comparison
`dose of mifepristone.
`Fertil Steril
`1991;56:32-40.
`World Health Organization.
`Termination
`of pregnancy
`with
`reduced
`doses of mifepristone.
`BMJ 1993j307:
`532-7.
`J-M, Girard
`J-P, Husson
`Bertagna X, Bertagna C, Luton
`glucocorti-
`F. The new steroid
`analog RU 486
`inhibits
`coid action
`in man. J Clin Endocrinoi
`Metab
`1984;59:
`25-8.
`AD, Lesiege D, Lariv-
`R, Oliveira
`Garrel DR, Moussali
`iere F. RU 486 prevents
`the acute effects of cortisol
`on
`glucose
`and
`leucm metabolism.
`J Clin
`Endocrinol
`Metab
`1995;80:379-85.
`M, Lah-
`0, Haukkamaa
`Luukkainen
`T, Heikinheimo
`and ovula-
`teenmaki
`P. Inhibition
`of folliculogenesis
`tion by the antiprogesterone
`RU 486. Fertil Steril 1988;
`49:961-3.
`Inhibi-
`H, Baird DT.
`VM, Hillier
`Ledger WL, Sweeting
`tion of ovulation
`by low-dose
`mifepristone
`(RU 486).
`Human Reprod
`1992;7:945-50.
`HD, Fuentealba
`Croxatto HB, Salvatierra
`AM, Croxatto
`low dose mife-
`B. Effects of continuous
`treatment
`with
`pristone
`throughout
`one menstrual
`cycle. Human
`Re-
`prod 1993j8:201-7.
`admin-
`P. Cyclic progestin
`Kekkonen
`R, Lahteenmaki
`istration
`brings
`about
`luteinization
`during
`continuous
`antiprogestin
`treatment.
`Contraception
`1996j53:193-5.
`Cameron
`ST, Thong
`KJ, Baird DT. Effect of daily
`low
`dose mifepristone
`on the ovarian
`cycle and on dynam-
`ics of follicle
`growth.
`Clin Endocrinol
`1995j43:407-14.
`Batista MC, Cartledge
`TP, Zellmer
`AW, Nieman
`Merriam
`GR, Loriaux DL. Evidence
`for a critical
`progesterone
`in
`the regulation
`of the midcycle
`tropin
`surge and ovulation.
`J Clin Endocrinol
`1992j74:565-70.
`Batista MC, Cartledge
`
`LK,
`role of
`gonado-
`Metab
`
`TP, Zellmer
`
`AW, Nieman
`
`LK,
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10
`
`11
`
`RU486 de-
`GR. The antiprogestin
`Loriaux DL, Merriam
`lays the midcycle
`gonadotropin
`surge and ovulation
`in
`gonadotropin-releasing
`hormone-induced
`cycles. Fertil
`Steril
`1994j62:28-34.
`LM, Yen SSC. Regres-
`AJ, Kettel
`12. Murphy
`AA, Morales
`the antiprogesterone
`sion of uterine
`leiomyomata
`to
`RU 486: dose-response
`effect. Fertil Steril 1995j64:187-
`90.
`AJ, Roberts V, Parm-
`LM, Morales
`AA, Kettel
`Murphy
`ley T, Yen SSC. Endometrial
`effects of long-term
`low-
`dose administration
`of RU 486. Fertil Steril
`1995j63:
`761-6.
`AW et al. Delayed
`TP, Zellmer
`Batista MC, Cartledge
`by daily administra-
`induced
`endometrial
`maturation
`RU 486: A potential
`new con-
`tion of the antiprogestin
`traceptive
`strategy. Am J Qbstet Gynecol
`1992;167:60-
`5.
`KJ, Dewar M, Mackie M, Baird DT.
`Glasier A, Thong
`Postcoital
`contraception
`with mifepristone.
`Lancet
`1991j337:1414-5.
`KJ, Dewar M, Mackie M, Baird DT.
`Glasier A, Thong
`Mifepristone
`(RU 486) compared with
`high-dose
`estro-
`gen and progestogen
`for emergency
`postcoital
`contra-
`ception. N Engl J Med 1992j327:1041-4.
`H,
`Heikinheimo
`0, Tevilin
`M, Shoupe D, Croxatto
`Lahteenmaki
`P. Quantitation
`of RU 486
`in human
`plasma
`by HPLC
`and RIA after column
`chromatogra-
`phy. Contraception
`1986;34:613-24.
`pharmacokinetics.
`Rowland
`M, Tozer
`TN. Clinical
`Concepts
`and applications.
`2nd ed. Philadelphia
`London:Lea
`and Febiger,
`1989:459-63.
`pharmacokinetics.
`Rowland
`M, Tozer
`TN. Clinical
`Concepts
`and applications.
`2nd ed. Philadelphia
`London:Lea
`and Febiger,
`1989:469-72
`Heikinheimo
`0, Ltihteenmaki
`PLA, Koivunen
`Metabolism
`and serum
`binding
`of RU 486
`after various
`single doses. Human Reprod
`85.
`I, Luuk-
`H, Spitz
`K, Croxatto
`0, Kontula
`Heikinheimo
`concentrations
`and
`P. Plasma
`kainen
`T, L&hteenm&ki
`receptor
`binding
`of RU 486 and
`its metabolites
`in hu-
`mans. J Steroid Biochem
`1987j26:279-84.
`and se-
`Wang JD, Shi WL, Zhang GQ, Bai XM. Tissue
`rum
`levels of steroid
`hormones
`and RU 486 after ad-
`ministration
`of mifepristone.
`Contraception
`1994;49:
`245-53.
`study of
`Shi YE, Ye ZH, He CH et al. Pharmacokinetic
`RU 486 and
`its metabolites
`after oral administration
`of
`single
`doses
`to pregnant
`and non-pregnant
`women.
`Contraception
`19933483133-49.
`Philibert
`D, Moguilevski
`M, Bonnat C, Busigny M, Pot-
`tier
`J. Influence
`of human
`alpha-l-acid
`glycoprotein
`of
`(AAG)
`on pharmacokinetics
`and biological
`activity
`RU 486.
`In: Abstracts
`of the 68th Meeting
`of the Endo-
`crine Society, Anaheim,
`CAj Abstract
`1006, Bethesda,
`MD:The
`Endocrine
`Society 1986:282.
`of the antiproges-
`Heikinheimo
`0. Pharmacokinetics
`terone RU 486
`in women
`during multiple
`dose admin-
`istration.
`J Steroid Biochem
`1989;32:21-5.
`ef-
`Spitz
`IM, Heikinheimo
`0, Wade CE. The divergent
`fect of RU 486 on adrenal
`function
`in the dog is related
`to differences
`in its pharmacokinetics.
`Acta Endocrinol
`1993j128:459-65.
`27. Jacqs-Aigrain
`
`and
`
`and
`
`E et al.
`in women
`1987j2:379-
`
`E, Panserat S, Sica L, Krishnamoorthy
`
`R.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`

`

`234 Kekkonen
`
`et al.
`
`Contraception
`1996:54:229-234
`
`Molecular genetics of cytochrome P-450 IID. Clin Rev
`Allerg Immunol 1995;13:211-21.
`28. Spatzenegger M, Jaeger W. Clinical importance of he-
`patic cytochrome P-450 in drug metabolism. Drug
`Metab Rev 1995;27:397-417.
`29. Heikinheimo 0, Kekkonen R. Dose-response relation-
`ships of RU 486. Ann Med 1993;25:71-6.
`30. Deraedt R, Bonnat C, Busigny M et al. Pharmacokinet-
`
`31.
`
`its of RU 486. In: Baulieu EE, Segal SJ, eds. The anti-
`progestin steroid RU 486 and human fertility control.
`New York:Plenum Press, 1985:103-22.
`Swahn ML, Cekan S, Wang G, Lundstrom V, Bygdeman
`M. Pharmacokinetic and clinical studies of RU 486 for
`fertility
`regulation. In: Baulieu EE, Segal SJ, eds. The
`antiprogestin steroid RU 486 and human fertility con-
`trol. New York:Plenum Press, 1985:249-58.
`
`