`
`Ehaxmawkinafls fimfiy 9% RE} 486 magi Em
`memeEimg $§§€§ {Kai admmigtmfisn Q§
`gingig dflgeg m megfiam and. nflnupz‘egmam
`
`waman
`
`angwen fifii‘, Zki-nfim; Ye‘, Cfiaflgwfiai Eel; Gazaaqiflg ghangl, iigmw
`@111 X311, REA» Van L99? (@3255 K, Eatirerbgfi
`
`1 Shanghai Institute Of Planned Parenthoad Rasearch, Shanghai; Pecple’s
`Repubiic Of China
`2 Speciai ngmmme of Ressml'ch, Develepmfint and Rasaamh Training
`in Human Reproduction, Warm Heah‘h Organization, Geneva,
`Switzerland
`
`3 R0373} i5303tgraduat€ Medical Schoni, Susana Reg-3d,. Landen, 33.14;.
`
`RU 486 am? three; 0f its zzmmbofitw {RU 42633 ~ mozzademetfiyi,
`RU 42848 ~ didemethyl, and RU 4.2698 - hydraxymembofimj were. deter-
`minea” by HPLC in magma ham nine Immpmgnam and 36 pregnant
`wamen Each nonnpmgnam subject £00k an oral dose of R U 486
`(25, 10(3, £108 and 690 mg cansecutiveiy) (may. per mensz‘ma} cycie.
`Six of £2.25 nine women also received a ($0.33 Of 200 mg. The; 36
`pregnant wamm were mndamizm’ in to four groups which warez given
`a singie dam Of 25, 280, 400 or 605) mg RU 4'86. Mood samples
`were taken up to 120 h aftgr (Easing. Peak concentratmns of RU 4:86
`05131233113 0;} mast occasiam; Within 2 i1. 1331231133 cancemmtmns
`
`a: I h and at .24 h increased in proportion to 10g d036, There- W’QS a
`wide variabflity {up to ten-few} 1'11 €335 phaz‘macakz’netic parama-
`mrs Within arch dose group. Plasma concentrw tjoris of RU 42633
`were similar to {how of R U 4'86 but concentrations 0f RU 42848
`and RU £12698 werg much EDI/var. AS with RU 486, ths plasma 8012:3311-
`tmu‘cms of the metabolites were maintained a: high leveis far
`
`.1993
`Submitted for pubiicatiom Eanuary 11,
`Accepted for pubhcatian lune: 18, 1993
`Address for correspondence: Dr PEA» Van Look, Speciai Programme: Of Rfissarch,
`Devaiopment and Research Training in Human Repmductian, World Heaith Orga-v
`nization, 1213 Geneva 27, Switzariand
`
`@ i993 B'utterwci'th»»fieinemann
`
`C013 traceptian 1993248, Aug.
`
`133
`
`

`

`C ’inica] Articie.
`
`up to 48—72 E: after aiming. The findings were consistent with a rapid
`membcfism of RU 4-86 m R U 42633; mmava! of the. sewnd methyl gmup
`wading t0 RU 42698 occurmd much more Slewly and to (1 much less
`extent than mmavai of the. firm. There appeared t0 Ewe no signifi-
`cant ciiffemrmes bgtween the, marl-magnum and pregnant wmnen in
`either the plasma cancentmtfims' or phaz‘macokinetic parameters
`0;” RU 486 and 1' 2:3 membefiws.
`
`wamds: Mifeprismm: {RU 486}, RU 486 metabolites, human pharmam-
`kinetics
`
`immductian
`
`l7fi-hydmxy—1l[H4~dimsthylamin0phenyljm17o:—
`RU 486 [mifspn‘smne;
`(l—pmpyny} E£31343,9-dien-31‘ma} is a potent amipm gestationa} stfimid {3,}
`which has bean Shawn to be effective in terminating early pregnancy,
`especially in mmbmatian with a prostagiandin {2—53. Three: metabolitres
`0f RU 486 have been. igientified éEig. M The compmmd undfirgues dameth—
`yiatisn to give the: mano- (RU 412633} and dip {RU 428483 (iemfitl‘nyiatad
`derivauvas as well as hydroxylatifin 0f the propynyi group {RU 426983"
`RU 486 and its metabolitcg can ha readily assayed in blflod by HPLC {63,
`
`RU 438
`
`RU 42698
`
`
`
`RU 42633
`
`RU 4258435
`
`111505OHM
`
`FsGUHE “i. RU 486 and its Wee: metabolites assayed in the preseni shady.
`
`13:4
`
`Comracepfiun 1993248, Aug,
`
`

`

`Mifepristone {RU 486) pharmaeoitineties:
`
`Sin" at a].
`
`and information is available regarding the blood concentrations: of the
`three metabolites in, nonpregnant women {79}. The results of these stntl~
`ies enggest that. the pharmaeohineties of RU 486 vary depending on the
`dose given, probably heeanse the compound binds to a high aifinitv~iirn-
`ited eanaeity binding protein in semen {8}. The absence of a proportional
`increase in the plasma concentrations of RU £186 following ingestion of
`larger doses may explain the laelt of a dose~response relationship when.
`the drug is. need alone tor the termination of early pregnancy {iii}.
`in order to further examine the pharrnaeoitineties of RU 486, the blood
`levels of the parent compound and its three main metabolites were niea~
`sured by HPLC after administration of various doses to the same group
`oi nonpregnant women, and the derived pharmaeokinetie parameters
`compared to those found in pregnant women taking similar doses oi the
`antiprogestin.
`
`thieeta and Methods:
`
`Perrniasion tor the study had heen granted hi] the Ethies Committees of
`the Shanghai institute for Planned Parenthood Research and oi the World
`l-iealth Organization, and informed consent was ohtained from the volun—
`tests after the purpose of the study and the procedures involved had been
`explained.
`Nine non—pregnant and 36 pregnant women were recruited. All subjects
`were healthy with no hisnoi")r of liver, renal, cardiovascular or endocrine
`diaeaae and none had taken any steroid-containing drugs for at least three
`months. The non—pregnant anhieets had had normal menstrual eyelet {29
`35 days} for at least three months prior to admission to the study. The
`pregnant Suhjeeta also had had regular menstrual eyelet: {25-35 dava} for
`at least three months prior to conception and, at the time of studv, had
`been amenorrhoeie for up to 49 days with an nltrasonographieallv eon--
`tinned, normal intrauterine pregnancy“
`Each non-pregnant suhieet received a dose of RU 41-86 once per menstrual
`cycle, three days before the expected time. of menses. The doses, adminis—
`tered consecutively, were $25, EGG, 400 and (Silt) mg. in six of the nine
`women, a dose of 1280 mg was also given, The pregnant subjects were
`randomized into four groups which were given a single dose or 25, 100,
`4-00 or drill) mg RU 486. The pregnancies were terminated hv vacuum
`aspiration after collection of the last blood sample.
`in both pregnant and non—pregnant women, hiood samples were taken
`from an anteenhital vein immediately before and ‘28 min, 49 min, i, 2!
`4,. 8, 12, 48, 72, 96 and iii) h after administration of RU 486. Heparin
`was used as anticoagulant and the plasma ohtained alter oentriiogation
`was stored at ~23¢C until analysed.
`RU 486 and its three metabolites were determined in the piasnta sain—
`
`Contrneeption 1993248, Aug.
`
`135
`
`

`

`Clinical Article
`
`pies by HFLC as described previeusly {63 with miner medifieatiens. All
`(338 reversed phase column EZGGmm x 3.5mm113} was used with a mellile
`phase (if methanul: methyleyanlde: water {42:
`’28: 30 by v01} at a flaw
`rate {ll 1 Ital/min. Recoveries 0E RU 486 and its; three metabolites»; RU 42633,
`R3 42698 and RU 42848 were 92%,. 93%,, 94% anal 64%, respectively, the
`Sensitivity 13f deteetien for: the {cur stemlds in plasma was 10 ng/mli and
`the intra~ am} interassay eeelficiems of variatien were < 10%. Adequate
`separation of the four stemida was achieved as illustratecl in Fig. 2“
`Plasma RU 486 concentratien-tlme curves were analysed by the item—
`tive method. With doses of 200 mg 01* less, the euwes were in agreement
`with a two—eempartment epen madel, whereas with higher defies, zem-
`mder kinetics applied for a period of abeut 48 ll alter campietien 0f the
`absm‘ptlen and dietrlbutlon phaSes. Acemdlngly, the values were cam»
`plated acemdlng t0 a n0n~eompartment mOdEl {11,112}. Clearance {Cl} was
`calculated fmm dese/AUC {area under the plasma eencentration—iime
`curves Obtained by the trapezoid rule), Volume 0f distrlbutlen {Veil was;
`calculated £er Clikel.
`
`Statlgtieal analysis. was dime by t~teet and differences were considered
`significant if P < €9.05: Because Of the size of the class: groups énlne WOmen),
`
`$64
`
`in: :47
`
`592
`
`
`
`.....____j m.‘.»___.,________,,,,,,
`
` J“810?
`
`, :37
`
`
`
`FEGURE 2. HPLC of RU 485 and its melaboiitee (a: RU 42848; b: RU 426953; CZ RU 42633; d: RU 486): A:
`blank piasma; E3: biank péasma with standards added; (3: plasma ebtained eight hours after a singie dose of
`1:30 mg RU 486.
`
`136
`
`Can trace-pile}; 1993 :48, Aug“
`
`

`

`Mifepriemne (RU 486,} phemiaeeicirieties:
`
`Shi’ er. all
`
`the study eeuld he expected t0 demenetrate differences between groups.
`of aheut
`1 SD {95% level “ewe-tailed teet; 99% power}. Based. en our
`previeue werh {6},
`this diserimimtory pewer weuld be sufficient m
`derrmn~ str‘ate difiereriees in phermaeekinetie parameters of hielegieai
`r’eleyanee.
`
`Reeuite
`
`Characteristics of suhieets
`
`There were rm significant differences in physieal characteristics between
`the greups studied {Table i}.
`
`Plasma levels at RU 486 end its Irietebofites
`
`Mean plasma mneemratiehs at RU 486 and its three metabolites at verb
`0113 times a‘iftii‘f are} administration 0i single dOSQS at RU 486 t0 “the nan-
`pregnant wemeri are shown in Fig. 3A. Abserptien at RU 486 was mpid,
`as illustrated by the presence at detectable amounts of the stereid in all
`2.8 min. samples 0i all subjects except see who received a 2-5 mg Liege.
`The rapiclity (if abeerptien was also shown by the finding that. peak plasma
`eeneeritratiens were achieveei at i h at less for El at the 42’. administratim’rs
`
`0i RU 486, between i and 2 h £01“ 15 administrations and after 2 h in only
`six. There was a very marked betweeneuhieet varietien in the piaema
`eeneerrtrzrtierie alter the same dose of RU 486, and examples at the size
`(if this variation are given for sortie sample times in Table 2. Deteetahle
`levels at RU 48-6 were {Guild in the 96 h samples 0i all wemen reeeiving
`296 mg or mere, in seven 0f the nine samples after 130 mg, but in name
`of the samples after the 25 mg deee.
`The ratio of the lh124h caneentratione it}: the five deees at RU 486
`
`decreased with inereaee in deee (25 mg, 5.8,- 190 mg, 3.5,- 200 mg, 22.9;
`409 mg, 2.6; 60%} mg, 2.4} suggesting that the rate of metaheiism decreased
`with increase in dose. This is also suggested by the data in Fig. 3A where
`
`TABLE 1.
`
`Phyeicai characteristics 31‘ euhieets (X t SE)
`
`Non"
`
`pregnant
`
`25~500
`
`Dese {mg}
`
`Pregnant
`
`25
`
`100
`
`
`400
`
`600
`
`Age (yrs)
`Height (em)
`Weight (kg)
`Body mase index
`
`283 t 5.1
`159.8 t 4.?
`55.4 -1-. 37.9
`21.? i 2.1
`
`29.1 r 3.3
`181.7 x 1.5
`54.8 1: 4.4
`20.7 : 1.7
`
`26.1 i 5.5
`152.31 : 3.8
`52.3 e 4.2
`€98
`: 1.?
`
`28.? i 4.8
`“31.4 i 3.8
`51.? 1*: 5.3
`19.8 i 1.5
`
`30.2 : 4.8
`181.0 3: 2.?
`53.5 '1'. 4.4
`26.6 ~1. 1.3
`
`Contraceptiem 1.993 :48, Aug.
`
`13,7
`
`

`

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`PLASMACONCENTRATEON(MG/ML
`
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`
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`PLASMACDNCENTRATEON(NF/ML
`
`100‘
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`
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`
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`975
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`TIMEHRS)AFTER ADMENEST‘EATEON
`
`R U 42 6313
`
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`48
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`96
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`T ME (HRS)- A'FE'ER ADMENESTRATEON
`
`FEGURE 2A4}: Mean {SEM} cansentrations of RU 466 {A} and its metabciiies (RU 42633: B; RU 42848: C; RU
`42698: D) after Esra! adminisiraténn of various doses 0? RU 488 m non~pregnam women.
`(Owe: 25 mg: g—v-«g: EOE) mg; Chm-D: 290 mg; «m»: 400 mg: VA]: 690 mg):
`
`for the higher doses:, in cantmst with the imwer doses, tbs steady decrease
`in pEasma Eevsls continues up :0 .96 - EZO h. Althuugh increasing the, dose,
`of RU 486 EfiCE m an increase in its mean pEasma cancemmtmng, this
`increase appeared 11112312th :3 (102:3 Thus. the. ratios. cf plasma concentra—
`EIEQI'ES at E E1 far {116: 25,100, EGG, 400 and 600 mg dases wera 1: E 9: 2 i:
`
`Contmcapmm 19:93:28, Aug.
`
`

`

`,fifiz‘feprismrm (R U 486} pharmacakinatics: Shi er: a].
`
`
`
`500
`
`
`
` 208 PLASMACONCENTRATKEN(MG/ML.)
`
`RU42848
`l
`
`
`
`1
`
`2
`
`4
`
`8
`
`12
`
`24
`
`48
`
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`
`96
`
`123
`
`TEME (HRS) AFTER ADMENESTRATiON
`
`
`\ l
`
`
`
`
`
`PLASMACONCENTRATEON(NGiML-
`
`R U 42693
`
`10
`
`'
`
`2 "Mwfimmmmmm—WW
`1
`2
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`3
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`48
`
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`
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`
`€20
`
`TEME (HHS) AFTER ADMENESTRATEON
`
`Rama 3 (amid).
`
`TABLE 2. Bameen—subject variation in piasma RU 488 cancentra’cima VaiueS are minimum amd maximum
`cmcgnirafions (ngfmi) at mu: seiected times 2mm administratimn of me varieus doses of RU 485 is) nm‘spregnam
`women
`
`
`
`{3058 {mg}
`
`25
`
`me
`
`200
`
`400
`
`590
`
`37~~~s489
`734088
`113-»859
`75-48?
`Guam
`Tfime 20 min
`1289-«2956
`41%2943
`7704840
`123m2€389
`594295
`1 h
`548—1328
`5934249
`3134077
`368—7181
`“swam
`8 h
`452-"? 083
`241-“?88
`97-»520
`8§~231
`31*? G3
`48 h
`
`
`Contraceptix’m 1.993 :48, Aug.
`
`139
`
`

`

`Ilinieal Article
`
`2.6: 3.2 eentparetl to date ratins at l: 4:, 8: 16: 24%. l-in‘wevet, there were
`significant correlations hetween leg rinse and l l1 plasma eeneentratlnns
`{R 2 {1,983, and between (lose and the ratie til plasma enneentratiens at l
`h £R=l).953. Similarly, there were significant correlations between log
`Close and 24, h plasma enneentratinns {R = (3.98), and between deae and the
`ratie eat the plasma. enneentratinne at 24 h {R=O.97}.
`Fig. fill shows the plasma caneentratinns nl the menndemethylatet‘l
`metabnlite. RU 42633 reached peak levels that were similar to those at
`RU 486, but the neat: was attained mete slowly. Thus, in ennttast with
`RU 486, peak concentrations nl RU 42633 were reached in less than 9;. h
`tor nnly two at the 4?; administrations at RU 486, item ’2, t0 L‘l h for 19
`administratinns, and after it h tnr 2L Exam 4 h after desing, mean plasma
`eoneenttatinns nl RU 42633 were greater than those at RU 486. Deteetahle
`levels at RU 42633 were present in the 96 h Samples after administration
`til lOO mg nr mete at RU 486 and in three Qt" the nine samples after the
`25 mg tinge“
`Peale eeneentratinns at RU 42848 (Fig. 3C} and RU 42698 {Fig 330} were
`nnly ahetit 25% (it these nl RU 4813 and Rll 42633 and Occurred much
`later. Thus, lnr 42, atlrninisttatinns at RU 486, peak enneenttatinns til RU
`42848. neentt‘ed in less than l2 h an 18 Occasions, between l2 and '24 h
`in 2210, and between .24 and 48 l1 in. tent. ln spite of the lower peak enneentta—
`tinns of RU 42848, deteetahle levels were lennd at 96 h in all Samples
`except nne, when the dose elf RU 486 was 160 mg er mere“ The times tn
`reach peak eeneenttatinne of RU 42698 were similar to these fer RU
`42633,. neetnring on six occasions in less than 2 h! between 2 and 4 h let
`l8 administrations, and after 4 h lnr l8. Plasma eeneenttatinne of RU
`42698 declined! mere quickly than these (if RU 42848,- deteetalrle levels
`were present at 96 h in all samples except ene after 2th mg or more of
`RU 486, in nnly one of the samples after 1th mg, and in name at the
`samples after 2.5 mg.
`Plasma eeneentratinns at RU 4R6 alter a single Oral rinse (it the Chain
`pennd t0 ptegnant women are shewn in Fig“ 4A and were net signifiean tly
`different from the correspnnding values in the nori~pregnant snhjeeteg
`Plasma enneenttatiene of the metahnlites ate. net presented in detail sinee
`they too did net (litter significantly between the pregnant and nannpregn
`nant wnn'ten. The values let the snhieets receiving the 690 my, time of
`RU 486: are compared in Fig. 43%.
`
`Phtirmaenkinetie pattern stem
`
`The calculated parameters for various doses 0f RU 486 in pregnant and non
`pregnant women are summarized in Table 3. Per wetnen in any partieulat
`rinse grnup, there was a wide variahility {up to ten-tnlrll in meat of the param-
`eters. For Crnax, same of the wnmen in the ZS—n‘ig rinse gtnnp had values
`
`MG
`
`{Senttneeptlnn 19R3;48, Ango
`
`

`

`Mifeprigtone {R U 4186) pharmacokinatics: Shi SE a}.
`
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`“ME (HRS) AFTER ADMiNiSTRATEON
`
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`
`FiGURE 4. A. Piasma cancentraiims of RU 486 after singie era: (Eases 0f RU 4% tr) pregnam wsmen.
`B. Pfasma mneenérafiims af RU 436 and HS metaboiiteas after ma! administratign 0? 500 mg RU 488 in pregnant
`warmen.
`
`C(mtmcepzian 1993248, Aug.
`
`141
`
`

`

`Ciinical
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`
`142
`
`Cumgmcepfion 1993
`
`48, Aug.
`
`

`

`Mitepristerie (R U 486} pharmaceltineties:
`
`Sill at al.
`
`almost as high as some at these who received see mg. Although Tatar
`shewet‘l wide intersuhieet variation within each dose group, the mean val~
`ties for the groups were net statistically significantly different. Values lor
`some parameters, egq Ctnax and AUC, were consistently higher in the non-
`pregnant than in the pregnant women for similar tieses, whereas the reverse
`was the ease for the clearance {Cl} values. The differences, hewever, were
`met statistically significant. Values for Tel arid Vcl were not different he:
`tween the pregnant and non—pregnant groups. Whilst it wenlcl he expected
`that values fer Cm as and AUC would increase wi lll‘i increase in clese, values
`fer Tel, Cl and Vii alse did, and the differences between the highest and
`lewest doses were statistically significant ll) < 0135},
`Dillereriees in the mean Ctriax values het‘weeri the lowest and highest
`closes of RU 486 were two~ t0 three—laid, hut for AUC the difference was
`ahniit ten-fold. This discrepancy arose heeanse Tel increased three— to
`inttr«lolti with dose, a change resulting from changes in Vii and Cl. which
`determine Tel. Both Val and Cl increased with rinsei the inerease in Vd
`Esire to minefield} being proportionately greater than that of Cl {approxin
`mately twe—lolt‘ll. The increase in Vd with ease suggests that RU 486
`hiritls only weakly to plasma pretein and that this binding is [if limited
`capacity. Clearance alse appeared t0 reach a limiting value at deses shove
`200 mg and this was prohahly the major factor in determining the elevated
`plasma levels at RU 486 over a long, duration. With doses of RU 486
`greater than 100 mg, plasma levels remained high tar up tn 48 h anti did
`net became undetectable for 96 to 120 h.
`
`Calculated parameters for the mrmorlemethylatetl (RU 45233), diale-
`rriethylatetl iRil 42848} and hydrnxylatetl till} 53-2698.) metabolites are
`shewri in Tables 4, 5 and 6, respectively.
`Values of Crnax for RU @2633 VVEIE similar to those all RU 486 {Tahle
`4), although the peak occurred later {mean ’l‘rnax about it; it let RU ass
`and 4.5 to 5 h for RU 42633} and, consequently, the serum levels remained
`higher tor a langer alteration. The findings are enrisistent with RU 42633
`being a rapidly termed metabolite at RU 485. RU 486 was also rapidly
`transiormetl to RU 42698 {mean Tmax about 4 h} {Table 5% but its plateau
`eoneerttratiens were. only sheet 23% of those at RU 486:3 suggesting that
`RU 42698 is only a mirror metabolite oi RU 486. its lewer serum concert
`tratiori was not tine re it being more rapidly metahelised since its Tel
`was not significantly different from that of RU 486. ill} 42848 (Table 5}
`shnwed. a clifferent pattern from the other metahnlites and reached Cmaxi
`which was only about 5% — 26% that oi RU 486 anti RU 42633, much
`more slowly {mean Tl‘i'iélx sheet l4 h). This suggests that the removal of
`the second methyl green is a. rnneh slower preeess than removal of the
`first, This slow removal of the second methyl group aeeetmts tor the.
`much lower plasma eerieeritrations at RU 4284-8, since the Tel for this
`rnetahelite was not significantly different from that of RU 4-2633.
`
`Centraeeptien 1993:48, Augw
`
`143
`
`

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`01:: 'i‘racgptiim 1993:
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`Cozz'igmceptjon 1Q93:48, Aug.
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`

`

`Mifepristmie {R U 486) itharmaeolrirretiea:
`
`3hr at til.
`
`.\
`
`lllaeussrrm
`
`The pharmaeukiuetles til various single dates have been previuuely (8)
`smelled in groups {if (littereut timinpreguaut women whereas in our study
`the deses were administered eeuaeeuti‘vely t0 the same wumen. As leuurl
`it: must previuus investigatiehs let 6}, ahserptieu ui RU 486 was rapid,
`with peak eeueeutratiena in meet women occurring hetweeu l and '2- h,
`irrespective of tluse. The serum censentratieus we fuuritl alert agree with
`these repurted previously.
`it: a study {83 of four diliereut doses (if RU 483 {Nil}, 4&0, (it‘ll) and 806
`mg}, there were. 11c: significant differences in plasma concentrations Within
`the first 48 h. in Our study, althuugh there was an overlay in the euueeutra-
`tioria with (luses (if it’ll) mg and above, the curves let the mean values let
`each tiese were differentiaterli This also applied to the plasma euueeutra-
`tiuua 0f the metal‘iulites. with the exception of. the til-rieurethylaterl eumn
`peuml. Lahteeumaki er al. (8} ieuml that with duses ahuve 100 mg, plasma
`eurieeutratiuua of RU 486 and the three metahelitcs Showed little aeerease
`
`during the first 48 h alter (lasing. Our iimlirrgs were similar with the
`exception til the 25 mg dose where a definite decrease. had. occurred by
`48 h and levels heeame uudeteetahle by 96 h. By 125'} h, levels after the
`three higher times {208, 403 and (3th mg) were still readily measurahle.
`Similar findings aepliecl t0 the plasma eeueeutratieua el the metabolites.
`Tel in our investigation increased with increase in close but this may
`he an artifaet clue tr) the difficulties or measuring this parameter accurately
`at. the higher duae levels. Our value for Tel {ahuut it) h} m hurt—pregnant
`wemeri after the 25umg tiese agreea with the mean value at aheut 25 it
`reported in previuus studies lei 6% using law closes (if RU 485. it this; is
`the approximate true rate at eliminatieu el RU 486, plaama cuneeutratiuue
`alter admiuistratiun at higher closes sheultl decline mere rapidly that}
`they (it). it: bleed, RU 486 binds to an upaeiri glycepreteirr £7}; this binding
`is weak - values of W are eat so low as re suggest tight. binding n and it
`is of limited capacity. Consequently, this weak binding is unlikely to
`aeeeuut fer the lung duration of the elevaterl plasma levels (Bl RU 486.
`The himliug alse appeara to he saturated at relatively law eunueutratiuus
`(ii RU 486.
`
`As peatulated previeusly {6? (in the hasis elf the V51, the lew clearance.
`and the much higher trausfer claustatrt item the inner to the peripheral
`eumpartmenr than from the peripheral to inner cumpartmeut, the pharma»
`culriuetie parameters suggest retentieu at RU 486 iii sume tissues from
`which the drug is enly sluwly released. "i”his is alau euppurted by Our data
`art the three major metabolites at RU 486; like the parent compelled,
`these metahelitea also maintain high serum concentrations ever extended
`perietls but they Show mueh lower binding to the glyeupruteiui This
`suggests that the hurtling of RU 486 to this protein titres not play an
`
`Contraceptierr 1993248, Aug.
`
`147
`
`

`

`Clinical Article
`
`important role in the low clearance of the aotiprogestio. RU 48.6, and to
`an even greater extent the demethylateti metabolites, are taken up 1'22 Vim
`by abdominal adipose tissue {13}, the concentration of RU 486 in adipose
`tissue being higher than that in. serum, altheugh for the metabolites the
`reverse is the case Considering that in the average subject depot adipose
`tissue may account for about 18% of total body weight, the amount of.
`RU 48.6 localising in this tissue may be considerable. After a dose of ECG
`mg RU 486, the. mean value let its concentration in abdominal adipose.
`tissue was 44'? rig/g {l3}; in a 65~ltg women, this would equate to about
`5.2 mg. l-iowever, this may be a minimal value since RU 486 may not
`localise to the same extent in the various fat depots in the hotly. For
`example, in animal experiments with ethynyl esttadiol, tlie ptopottioii
`of the dese detected in various lat depots varied widely, with that in
`mesetiteric tat being about five times that in abdominal fat {14}
`’I‘here were no significant differences ii} the plasma concentrations or
`phstmztcokitietic parameters of RU 486 anti its metabolites between the
`neo—ptegnamt and pregnant women
`The finding that increasing the dose of RU 486 from 288 to 609 mg
`produces little increase in its plasma concentmtions for up to 7'2 h might
`suggest that, clinically; the lower dose should be as effective as the hith
`one. Also, little it anything wettlcl probably be gained by giving multiple
`closes of RU 486 instead (if a single close. Recently reported data on the
`efficacy of different multiple and single doses of RU 486, used in comlaina—
`tion. with the ptostaglant‘lin analogue gemeptost for termination of early
`pregnancy, support these conclusions {15,16}.
`
`Aeksewletfigmeots
`
`This investigation received financial support flow: the Special Programme
`tot Research, Development end Research Training in Human Reproduc—
`tion of the World Health Organization. Mt liang Nai~xiong ot the Shanghai
`institute of Cemputei Technology assisted with the data analysis and
`Mrs Bai Xiu-mei of the Shanghai institute for Planned Parenthood Re-
`search with the steroid assays. Skilltul assistance in preparing the manu—
`script for publication was provided lay Mrs B. Fontaine. Tablets of EU
`4-86 and reteteiice samples at the compound and its metabolites were
`kindly provided by Roussel~Uclel, Paris, France.
`
`Retetetiees
`
`l. Pliilibert D, Moguilewslty M. Mary 1 at :11. Pharmacological motile oi‘ RU 486
`in animals. In: Beulieu EE, Segal S}, eds. The Antiprogestin Steroid R U 11813
`and Human Fertility Control. New York: Plenum Press, 1985: 494318.
`2.. Bygdeman M, S‘Wahfl ML. Progesterone receptor blockage. Effect on uterine
`centtsctility and early pregnancy. Contraception 1985; 3‘2: 45%}.
`
`1153-8
`
`Centracegjtion EQQSMES, Aug.
`
`

`

`C»)
`
`U“.
`
`Mifepriszone {RU 486) phannacokinezias:
`
`3111' a: a1.
`
`. Cameron 1’?, Michic AF, Baird DT. Thszrapentic abortion in earfiy pregnancy
`with antipmgastogan RU 485 31mm: or in combination with pmstagiamiin
`analogus {Gemeprost}. Contracapn'nn 1,9863; 34: 455168.
`Duboiss C, UEmann A, Aubeny F. at .511. Contragestion par 1e: RU 486: intérét
`1:1: E’associanon 51 um dérivé prostaghmdine. C R Acad Sci (Paris) 1988; 336:
`57-61,
`
`6.
`
`. Fun CR Van Look "PEA. N e'w1y developed competitive progesterone: antago»
`nists for ferflity confirm. Front Horm R63 1991; 19: 1.27~(5?.
`He Chang-1131, Shi Yongwen, Ye. Zhbhou at a}. Pharmacokinetic study of oraiiy
`administered RU 4-86 in non-pregnant woman. Contraception 1.98.9,- 4-0: 449—
`60.
`
`Heikinhezimo C), Lé‘nmen méiki FLA, Koivnnon E 6t :71. Metabolism and serum
`binding of RU 486 in women after vanons gingEE doses. Hum 86:33:05? 1987;
`2: 37985.
`
`. Léhteenméki 13’, Heikinheimn O, Croxatto H at a}. Pharmamkimttics and
`metabohsm of RU 486. ,1 Steroid Biachem 1987,- 1117: 859~63.
`Cekan S, Aodo A112, Sagerstéen E, Van Look FFA, Mesainis 1,. Templeton A.
`Lovels of the antiprogentin R11 486 and its metabolites in human 1310061 and
`foiiicnlm‘ fluid fol1ow'mg oral adminigtration 01: a sing1c3 dose. Hum Roi. Iod
`1989; 4: 131—5.
`Van Look FFAJ Bygdeman M. Antipmgeswtionai steroids: 3 new dimension in
`human Fartiiity regn1ation. In: Mulligan S, Ed. Oxford Reviews of Reproductiwj
`Biology. Volume 11. Oxford: Oxford University 131655, 1989: 1-60,
`Gihakii 1V1, Farrier D. Fharmacokinetics. New York: E'Eekker, 1982
`Yamaoka K, Nakagnwa '1‘, Una T. Statisticai momentfi in pharmaeokinetics,
`I Phannacokinet Biopharm 19.78; 6: 54?»?36.
`Heikinhcimo O, Haukkamaa M, Lifihtecnméki 1’. Distribution 01 RU 486 and
`its demethymted metabolites in humans. ,1’ Chi: Endocrinof Metab 1989; 68:
`270-5.
`
`11').
`
`11.
`12.
`
`13.
`
`14.
`
`16.
`
`Razed M}, Fotharby 1i. Metabohsm of ethynyinastradiafi in the guinoanpig. ,’
`Steroid Biochem 1975; 6: 1216.
`. Worid Hoaith Organization. Fragnancy termination with mifeprigtone and
`gemoprogtz a mu1ticenter comparison between mpeated doses and a Single.
`(1036. of mifnpnstone. Fem} Sign] 1991;. 56: 332-40.
`Van Look FFA, V0121 Herman 11. Antipmgestins infertility reguiation. Magyar
`Nérvomk Lézpia 1992; 55: 2150.2.
`
`Comrncepnon 1993:48, Aug.
`
`1519
`
`