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Pharmacokinetic study of orally administered RU 486 in non-pregnant women
PRARMACOKINETIC
STUDY OF ORALLY ADMINISTERRD IN NON-PREGNANT WOMEN
RU
486
He Chang-hail, Shi Yong-en', Ye Zhi-houl, Zhang Guo-qingl, Jiang Nai-xiong', P.F.A. Van Look3 and K. Fotherby4
Parenthood 'Shanghai Institute of Planned Shanghai, People's Republic of China
Research,
'Shanghai Institute of Computer People's Republic of China
Shanghai,
Technology,
3Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland 4Royal Postgraduate Medical School, Ducane Road, London, England Abstract
A method based on HPLC was devised for the estimation blood and utilised to study the of RU 486 in pharmacokinetics of a single dose of 50 mg RU 486 administered orally to 12 women on day 7 of the cycle. The dose was rapidly absorbed with peak plasma concentration between 1 and 2 hours. Distribution was also rapid (mean tt,a:1.4h), whereas elimination was slow (mean t$(3:28.3 h). RU 486 was still detectable in some women at 72 h after administration. The plasma concentrations fitted the equation for a two-compartment open model from which the pharmacokinetic parameters were calculated. The mean total plasma clearance was 3.0 l/h, and the comparison of our data published studies suggests that the with those pharmacokinetics of RU 486 in Chinese women are similar to those of other populations. Address for correspondence: P.F.A. Van Look, M.D., Ph.D., Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, 1211 Geneva 27, Switzerland. Submitted for publication May 25, 1989 Accepted for publication June 28, 1989
OCTOBER 1989 VOL. 40 NO. 4
CONTRACEPTION
Introduction 486 (mifepristone, 17S-hydroxy-llS-(4-dimethylRU aminophenyl)-17a-(l-propynyl)-oestra-4,9-dien-3-one) is a 19-norsteroid and, because of its great affinity for progesterone and glucocorticoid receptors, it is a potent antiprogesterone and antiglucocorticoid agent (1). Due to the former effect, clinical trials have demonstrated its early pregnancy terminating effectiveness in (2-5), especially when combined with a prostaglandin (6). The dose used is usually 50 mg or more, which has the advantage that RU 486 can be measured in plasma by HPLC. Since RU 486 has not previously been studied in Chinese women, a method for and applied to a estimation was developed its pharmacokinetic study. Subjects and Methods pharmacokinetic studies were performed, each TWO involving six healthy women aged 23-43 years. Their heights ranged from 157-166 cm (mean: 160 cm): their weights from 44-67 kg (mean: 5J.52 kg), and their body mass indices (weight (kg)/height (m )) from 17.8-26.8 (mean: 22.3). All subjects had normal regular menstrual cycles, were not taking any steroid-containing drugs, and had no history of liver, renal, cardiac, or endocrine disease. Local ethical committee approval had been granted for the studies and informed consent was obtained from each woman. Each subject fasted for at least one hour before and at least one hour after oral administration of one tablet of 50 mg RU 486 at about 08.00 h on day 7 of a menstrual cycle. In 'the first study, blood samples (5-8 ml) were taken from an antecubital vein immediately before and at 1, 2, 4, 8, 12, 24, and 48 h after drug administration. In the second study, additional samples were taken at 0.33, 0.5, 0.75, and 72 h. Heparin was used as anticoagulant and the plasma obtained after centrifugation was stored at -2OOC until analysed. RU 486 was estimated by HPLC (7). In brief, RU 486 was extracted from plasma (0.05-2 ml) with 5 ml diethyl ether. The mixture was frozen in solid CO in acetone and the ether phase decanted into a dry silanise3 tube. The thawed plasma was re-extracted with ether, and the two ether extracts were combined and evaporated to dryness. The residue was dissolved in 125-250 ~1 of mobile phase (methanol:water, 4~1 by vol.) and 50 ~1 injected directly into the HPLC. stainless steel column (200 mm x 5 mm ID), packed wit: octadecane silicone on 10 pm YWG as support, was used. The flow rate was 1 ml/min and the UV detector was set at 320 nm.
460
OCTOBER 1989VOL. 40 NO. 4
CONTRACEPTION
A typical standard curve is shown in Fig. 1.
concentration (ng/ml)
Fig. 1. Concentration-response curve for HPLC of RU 486.
The limit of sensitivity (the minimum concentration detectable above background) was 36 ng/ml. Reproducibility of the method, tested on replicate samples at each of two concentrations (240 and 1200 ng RU 486/ml) was good, with a coefficient of variation of 4.9%. Recovery of RU 486 added to 1 ml of blank plasma was high: 95.4 + 3.3% (mean + SD) for 1200 ng/ml and 94.2 + 3.7% for 240 ng/ml for 6 estimates at each dose level in duplicate. Typical chromatograms of plasma extracts are shown in Fig. 2. Plasma concentrations of RU 486 fitted the equation for a two-compartment open model: C =
where C A
= =
B
=
a
=
$ = Ka = t =
Aeeat + Be-St- (A+B)e-Kat
plasma concentration plasma concentration at time 0 for rapid disposition curve plasma concentration at time 0 for slow disposition curve first order rate constant for disposition from central to peripheral compartment elimination rate constant first order rate constant for absorption time after administration
OCTOBER 1989 VOL. 40 NO. 4
451
CONTRACEPTION
3
I
Lno
NU
Pig. 2. HPLC of plasma extracts (A: Control plasma; B: control plasma with added RU 486; C: plasma from subject at 8 h after oral administration of RU r86r Results Plasma concentrations of RU 486 in the two groups of women are shown in Table I. Since there were no significant differences between the values in the two studies, the results were combined and mean values for the whole group are given in Fig. 3. The results show that RU 486 was rapidly absorbed with significant amounts present in the 20 min samples and peak concentrations (Cmax) at 1-2 h. In contrast, elimination was slow and significant amounts of RU 486 were still detected in most women at 72 h. Calculated pharmacokinetic parameters for the 12 women are The rapid absorption is illustrated by shown in Table II. the small values for Ka and Tmax (the time to peak concentration), the latter varying from 1.1-2.5 h except in subject 4 in whom absorption was slow. Consequently, this
OCTOBER 1989VOL. 40 NO. 4
-
972
627
435
255
204
155
63
0.75
1
2
4
8
I2
24
46
B
-
0.50
72
_
0.33
E P
Tii after hsinp (hi
1
I
i?
lil 5
d
W
d ii
:
264
365
375
468
696
1140
503
-
2
62
203
290
405
578
1204
1374
-
3
152
293
372
445
766
432
-
-
4
PLASMA CONCENTRATIONS
181
298
316
392
618
1143
1712
_
6
158
258
333
394
540
925
1573
-
6 232
7
50
60
163
230
272
392
590
1312
1358
1352
subied
<36
43
139
245
441
573
1093
800
233
73
24
8
40
a0
167
203
344
466
1162
796
603
360
109
9
~36
~36
70
144
255
283
611
842
564
438
50
10
TABLE I (NGIML) OF RU 466 AFTER ADMINISTRATION
56
II9
215
323
464
557
1353
608
365
160
47
11
61
96
208
287
320
500
650
367
361
190
56
12
OF A 50 MG DOSE
34
110
212
277
371
535
927
987
581
429
87
: .__I--_
Mean
72
80
135
300
445
405
472
76
SD
s
8 -r
F;
;;f
00 z
CONJRACEPJlON
. 0
OCTOBER 1989 VOL. 40 NO. 4
Vd (1) VI (1) AUCO-a‘ x10' K12 K21 KIO
(mglml) bath) Wfh) Q(h) Cl(Vh)
Tmax (h) CIIMX
;xw
AxlO" B Ka
Parameter
0.7 1.0 15.6 3.3 74 15.2 15.3
0.40 0.15 0.21
0.31 0.09 0.05
0.53 0.12 0.17
10.5 525 0.99 0.72 4.4 1.3 1.53
4.6 456 0.75 0.44 1.1 2.5 1.26
0.9 1.6 64.4 1.1 100 20.3 46.4
3
2
0.6 0.9 27.6 3.7 149 22.1 13.3
7.2 279 1.10 0.79 2.5 1.2 1.04
1
0.12 0.09 0.07
1.9 2.7 27.5 2.1 65 30.1 23.4
3.6 506 0.37 0.25 2.5 4.6 0.65
4
0.56 0.09 0.14
0.59 0.11 0.15
0.6 0.6 33.5 2.1 100 13.4 24.2
14.1 426 1.99 0.63 2.1 1.1 1.66
12.7 405 1.06 0.77 1.6 1.2 1.65 0.6 0.9 42.7 1.7 105 12.4 29.3
6
5
0.16 0.11 0.17
0.57 0.12 0.22
0.19 0.07 0.15
1.1 1.6 26.1 3.1 116 20.2 16.3
5.6 293 0.63 0.36 2.6 2.2 1.21
4.7 440 0.64 0.39 4.6 2.2 1.13 1.1 1.6 14.3 3.6 79 22.4 13.1
9
6
0.6 0.6 23.6 3.5 121 16.1 14.1
12.3 326 1.14 0.66 2.9 1.1 1.36
7
0.9 1.5 25.2 2.4 66 17.3 20.6 0.24 0.09 0.14
0.42 0.12 0.27
5.7 429 0.76 0.44 2.7 2.4 1.46
11
0.7 0.9 16.1 6.6 154 24.6 7.5
7.6 232 1.01 0.77 4.3 1.2 0.91
10
0.26 0.12 0.11
0.9 1.5 22.6 3.1 101 27.1 16.1
3.6 415 0.75 0.46 3.1 2.5 0.95
12
0.36 0.11 0.15
0.9 1.4 26.3 3.0 106 29.1 29.0
7.7 395 0.66 0.59 2.9 2.0 1.27
MearI
0.17 0.02 0.06
0.4 0.6 13.6 1.4 25 5.5 10.2
3.7 92 0.24 0.22 1.1 1.1 0.32
SD
T
TABLE II PHARMACOKINETIC PARAMETERS FOR RU 486 AFTER ORAL ADMINISTRATION OF A 60 MG DOSE ( V?: VOLUME OF CENTRAL COMPARTMENT; FOR OTHER ABBREVIATIONS SEE TEXT. )
CONTRACEPTION
half-life of value for the also had a high subject Omitting the values from subject 4, distribution (tL,a). not marked, with most variability was inter-subject two-fold range. However, showing only a parameters (area under plasma bioavailability as assessed by AUC concentration-time curve), and plasma clearance (C) showed a Tmax and U-;a showed the largest much greater variability. inter-subject variability. Values for the apparent volume of distribution (Vd) suggest that, although some binding such as to were Values occurred, RU 486 was not extensively bound in blood. for clearance were low, showing that elimination of RU 486 from the circulation was slow, which accounts for the long elimination half-life (t$p) and low value for the elimination rate constant (KlO). There mass index and tt2p and significant
were no significant correlations between body and t%P, Cmax, Vd, Cl and AUC, or between Cmax AUC; but the correlation between AUC and Cl was (pcO.01). Discussion
A number of studies on the pharmacokinetics of RU 486 has already been published (8-15), but in view of clinical studies in progress with this compound in Chinese women of (16), it seemed important to study the pharmacokinetics RU 486 in this population. It is difficult to compare the various studies because of the different doses of RU 486 which have been used, the different methods employed for the estimation of serum or plasma RU 486 concentrations, and the number of subjects enrolled in small the studies. Radioimmunoassay methods tend not to be as specific as HPLC due to cross-reaction with metabolites of RU 486 but in one study (10) there was a good correlation between the two methods. Some relevant results from previous single-dose studies are compared with our data in Table III. There is reasonable agreement between the different values for the maximum concentrations (Cmax) achieved in spite of the various doses used. Also, all studies show that the time required (Tmax) to achieve Cmax is low, indicating rapid absorption of the dose. As shown in Table II, the mean value for the half-life of absorption (t%a) was less than 1 h. Distribution was also rapid, the mean half-life of distribution being 1.4 h, but elimination was slow. Serum concentrations were still high 24 h after dosing, and in a number of studies, measurable amounts of RU 486 were detectable in serum for more than 5 days, although in our study, concentrations were very low in the final samples taken at 3 days. These findings reflect the long t%2p of RU 486, the mean value from the studies in Table II (excluding
OCTOBER 1989 VOL. 40 NO. 4
HPLC
Presen
12
15
-
4ikg
14
HPLC
50
3
50
13
ARA
HPLC
11
25lkg
RRA
4
11
to/kg
12
HPLC
200
5
100
IO.11
RIA
RIA
2
50
9
RIA
Method
6
3
100
No. 01
subjed
Dose
ow)
8
Ref.
1
1.7-2.5
1.3io.3
4.9i1.2
2.Okl .I
1
1.5
3.1&1.9
7.5k2.9
3.9kO.4
2.5kl.O
16-36
0.2-0.8
0.2iO.l
1.8&4
19.227.0
0.3iO.l
28.3k13.8
29.1&3
53.76.9
20.6i7.7 0.2iO.l
>27
24
l-2
23.7k3.0
0.520.1
(mg/mb
C24h
0.7*0.1
(h)
Tmax
5.2k1.8
1.9io.4
1.e*o.r
m&w
Cmax
TABLE III PHARMACOKINETIC STUDIES WITH RU 486 (RRA: RADIORECEPTOR ASSAY; RIA: RADIOIMMUNOASSAY; C24H: SERUM CONCENTRATION AT 24 HI
CONTRACEPTION
The longer value ref. 14) being approximately 25 h. reported in ref. 14 may be due to use of a non-specific assay which may have included metabolites of RU 486. As in our study, two other studies (8,13) found that their analytical data fitted a two-compartment open model for pharmacokinetic analysis, whereas Liu et al. (14) used Values analysis. for various non-compartmental pharmacokinetic parameters derived from our data are shown in Table II. Only two other studies have derived any Values for clearance were pharmacokinetic parameters. reported as approximately 1.4 l/h (8) and 1.0 l/h (14) compared to our mean value of 3.0 l/h. Our value for the apparent volume of distribution Vd (106 1) agrees with the value of 90 1 reported by Liu et al. (14). Values for Vd are not so low as to suggest tight binding to serum proteins. Studies (8,12,17) have shown more than 95% of RU 486 in serum to be bound, but there is controversy about the binding protein. Some (8,12) have suggested albumin, whereas others (17) postulate al-acid glycoprotein. Binding of RU 486 to either of these proteins is unlikely to be high affinity, and it is possible that when higher doses of RU 486 are used the acid glycoprotein becomes saturated and albumin then becomes the major binding protein. The values for Vd, therefore, might suggest tight binding of RU 486 to tissue proteins. This would be substantiated by (i) the low clearance and long half-life of elimination of RU 486 and (ii) the higher value for K12 than for K21, suggesting that transfer from the central to a peripheral compartment was more rapid than the reverse. The long half-life and low clearance are unlikely to be due to difficulty in metabolizing RU 486 since metabolites of the compound reach peak concentrations in serum within l-2 h (11). The comparison of our data with that of others (Table III) suggests that the pharmacokinetics of RU 486 in Chinese women do not differ from those of other populations. Acknowledgements This investigation received financial support from the World Health Organization's special Programme for Research, Development and Research Training in Human Reproduction. Ru 486 was kindly provided by Roussel-Uclaf, Paris, France.
OCTOBER 1989 VOL. 40 NO. 4
CONTRACEPTION
References 1.
Baulieu EE. RU 486: an antiprogestin steroid with contragestive activity in women. In: Baulieu EE, Segal eds. The antiprogestin steroid RU 486 and human SJ, fertility control. New York: Plenum Press, 1985;1-25.
2.
Herrmann W, Wyss R, Riondel A, et al. Effet d'un steroide anti-progest&rone chez la femme: interruption du Cycle menstruel et de la grossesse au debut. CR Acad Sci (Paris) 1982;294:933-8.
3.
Termination of very Kovacs L, Sas M, Resch BA, et al. early pregnancy by RU 486 - an antiprogestational Contraception 1984;29:399-410. compound.
4.
Brenner PF, et al. Mishell DR Jr, Shoupe D, Termination of early gestation with the anti-progestin Contraception steroid RU 486: medium versus low dose. 1987;35:307-21.
5.
Early pregnancy termination Birgerson L, Odlind V. with antiprogestins: a comparative clinical study of RU Fertil 486 given in two dose regimens and Epostane. Steril 1987;48:565-70.
6.
Van Look PFA, Bygdeman M. Antiprogestational steroids: a new dimension in human fertility regulation. In: Oxford Reviews of Reproductive Milligan SR, ed. Press, Vol. 11. oxford: Oxford University Biology, 1989; in press.
7.
High performance liquid Ye 2, Zhang G, Bai X. 486 in human determination of RU chromatographic Chin J Chromatogr 1987;3:179-82. plasma.
8.
Busigny M, et al. BOnnat C, Deraedt R, Phannacokinetics of RU 486. In: Baulieu EE, Segal SJ, steroid RU 486 and human eds. The antiprogestin New York: Plenum Press, 1985;103fertility control. 22.
9.
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 New York: Plenum Press, 1985;249-58. control.
10.
H, Shoupe D, Croxatto M, Heikinheimo 0, Tevilin Quantitation of RU 486 in human plasma Ghteenm3ki P. column chromatography. HPLC RIA after and by Contraception 1986;34:613-24.
OCTOBER 1989 VOL. 40 NO. 4
469
CONTRACEPTION
11.
Heikinheimo 0, Kontula K, Croxatto H, Spitz I, Luukkainen T, L;ihteenmskiP. Plasma concentrations and receptor binding of RU 486 and its metabolites in humans. J Steroid Biochem 1987;26:279-84.
12.
Kawai S, Nieman LK, Brandon DD, Udelsman R, Loriaux DL, Chrousos GP. Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man. J Pharmacol Exp Ther 1987;241:401-6.
13.
Lghteenmski P, Heikinheimo 0, Croxatto H, et al. Pharmacokinetics and metabolism of RU 486. J Steroid Biochem 1987;27:859-63.
14.
Pharmacodynamics of the Liu JH, Garzo VG, yen SSC. after oral RU486 in women antiprogesterone administration. Fertil Steril 1988;50:245-9.
15.
antiPharmacokinetics of the Heikinheimo 0. progesterone RU 486 in women during multiple dose administration. J Steroid Biochem 1989;32:21-5.
16.
Gao J, Qiao G-M, Wu Y-M, et al.
17.
Heikinheimo 0, Lshteenmgki PLA, Koivunen E, et al. Metabolism and serum binding of RU 486 in women after various single doses. Hum Reprod 1987;2:379-85.
Pregnancy interruption 486 in combination with dl-15-methylwith RU ~i;;;;z:;~;;; F&8q;;hz;5e;:er: the Chinese experience.
OCTOBER 1989 VOL. 40 NO. 4
STUDY OF ORALLY ADMINISTERRD IN NON-PREGNANT WOMEN
RU
486
He Chang-hail, Shi Yong-en', Ye Zhi-houl, Zhang Guo-qingl, Jiang Nai-xiong', P.F.A. Van Look3 and K. Fotherby4
Parenthood 'Shanghai Institute of Planned Shanghai, People's Republic of China
Research,
'Shanghai Institute of Computer People's Republic of China
Shanghai,
Technology,
3Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland 4Royal Postgraduate Medical School, Ducane Road, London, England Abstract
A method based on HPLC was devised for the estimation blood and utilised to study the of RU 486 in pharmacokinetics of a single dose of 50 mg RU 486 administered orally to 12 women on day 7 of the cycle. The dose was rapidly absorbed with peak plasma concentration between 1 and 2 hours. Distribution was also rapid (mean tt,a:1.4h), whereas elimination was slow (mean t$(3:28.3 h). RU 486 was still detectable in some women at 72 h after administration. The plasma concentrations fitted the equation for a two-compartment open model from which the pharmacokinetic parameters were calculated. The mean total plasma clearance was 3.0 l/h, and the comparison of our data published studies suggests that the with those pharmacokinetics of RU 486 in Chinese women are similar to those of other populations. Address for correspondence: P.F.A. Van Look, M.D., Ph.D., Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, 1211 Geneva 27, Switzerland. Submitted for publication May 25, 1989 Accepted for publication June 28, 1989
OCTOBER 1989 VOL. 40 NO. 4
CONTRACEPTION
Introduction 486 (mifepristone, 17S-hydroxy-llS-(4-dimethylRU aminophenyl)-17a-(l-propynyl)-oestra-4,9-dien-3-one) is a 19-norsteroid and, because of its great affinity for progesterone and glucocorticoid receptors, it is a potent antiprogesterone and antiglucocorticoid agent (1). Due to the former effect, clinical trials have demonstrated its early pregnancy terminating effectiveness in (2-5), especially when combined with a prostaglandin (6). The dose used is usually 50 mg or more, which has the advantage that RU 486 can be measured in plasma by HPLC. Since RU 486 has not previously been studied in Chinese women, a method for and applied to a estimation was developed its pharmacokinetic study. Subjects and Methods pharmacokinetic studies were performed, each TWO involving six healthy women aged 23-43 years. Their heights ranged from 157-166 cm (mean: 160 cm): their weights from 44-67 kg (mean: 5J.52 kg), and their body mass indices (weight (kg)/height (m )) from 17.8-26.8 (mean: 22.3). All subjects had normal regular menstrual cycles, were not taking any steroid-containing drugs, and had no history of liver, renal, cardiac, or endocrine disease. Local ethical committee approval had been granted for the studies and informed consent was obtained from each woman. Each subject fasted for at least one hour before and at least one hour after oral administration of one tablet of 50 mg RU 486 at about 08.00 h on day 7 of a menstrual cycle. In 'the first study, blood samples (5-8 ml) were taken from an antecubital vein immediately before and at 1, 2, 4, 8, 12, 24, and 48 h after drug administration. In the second study, additional samples were taken at 0.33, 0.5, 0.75, and 72 h. Heparin was used as anticoagulant and the plasma obtained after centrifugation was stored at -2OOC until analysed. RU 486 was estimated by HPLC (7). In brief, RU 486 was extracted from plasma (0.05-2 ml) with 5 ml diethyl ether. The mixture was frozen in solid CO in acetone and the ether phase decanted into a dry silanise3 tube. The thawed plasma was re-extracted with ether, and the two ether extracts were combined and evaporated to dryness. The residue was dissolved in 125-250 ~1 of mobile phase (methanol:water, 4~1 by vol.) and 50 ~1 injected directly into the HPLC. stainless steel column (200 mm x 5 mm ID), packed wit: octadecane silicone on 10 pm YWG as support, was used. The flow rate was 1 ml/min and the UV detector was set at 320 nm.
460
OCTOBER 1989VOL. 40 NO. 4
CONTRACEPTION
A typical standard curve is shown in Fig. 1.
concentration (ng/ml)
Fig. 1. Concentration-response curve for HPLC of RU 486.
The limit of sensitivity (the minimum concentration detectable above background) was 36 ng/ml. Reproducibility of the method, tested on replicate samples at each of two concentrations (240 and 1200 ng RU 486/ml) was good, with a coefficient of variation of 4.9%. Recovery of RU 486 added to 1 ml of blank plasma was high: 95.4 + 3.3% (mean + SD) for 1200 ng/ml and 94.2 + 3.7% for 240 ng/ml for 6 estimates at each dose level in duplicate. Typical chromatograms of plasma extracts are shown in Fig. 2. Plasma concentrations of RU 486 fitted the equation for a two-compartment open model: C =
where C A
= =
B
=
a
=
$ = Ka = t =
Aeeat + Be-St- (A+B)e-Kat
plasma concentration plasma concentration at time 0 for rapid disposition curve plasma concentration at time 0 for slow disposition curve first order rate constant for disposition from central to peripheral compartment elimination rate constant first order rate constant for absorption time after administration
OCTOBER 1989 VOL. 40 NO. 4
451
CONTRACEPTION
3
I
Lno
NU
Pig. 2. HPLC of plasma extracts (A: Control plasma; B: control plasma with added RU 486; C: plasma from subject at 8 h after oral administration of RU r86r Results Plasma concentrations of RU 486 in the two groups of women are shown in Table I. Since there were no significant differences between the values in the two studies, the results were combined and mean values for the whole group are given in Fig. 3. The results show that RU 486 was rapidly absorbed with significant amounts present in the 20 min samples and peak concentrations (Cmax) at 1-2 h. In contrast, elimination was slow and significant amounts of RU 486 were still detected in most women at 72 h. Calculated pharmacokinetic parameters for the 12 women are The rapid absorption is illustrated by shown in Table II. the small values for Ka and Tmax (the time to peak concentration), the latter varying from 1.1-2.5 h except in subject 4 in whom absorption was slow. Consequently, this
OCTOBER 1989VOL. 40 NO. 4
-
972
627
435
255
204
155
63
0.75
1
2
4
8
I2
24
46
B
-
0.50
72
_
0.33
E P
Tii after hsinp (hi
1
I
i?
lil 5
d
W
d ii
:
264
365
375
468
696
1140
503
-
2
62
203
290
405
578
1204
1374
-
3
152
293
372
445
766
432
-
-
4
PLASMA CONCENTRATIONS
181
298
316
392
618
1143
1712
_
6
158
258
333
394
540
925
1573
-
6 232
7
50
60
163
230
272
392
590
1312
1358
1352
subied
<36
43
139
245
441
573
1093
800
233
73
24
8
40
a0
167
203
344
466
1162
796
603
360
109
9
~36
~36
70
144
255
283
611
842
564
438
50
10
TABLE I (NGIML) OF RU 466 AFTER ADMINISTRATION
56
II9
215
323
464
557
1353
608
365
160
47
11
61
96
208
287
320
500
650
367
361
190
56
12
OF A 50 MG DOSE
34
110
212
277
371
535
927
987
581
429
87
: .__I--_
Mean
72
80
135
300
445
405
472
76
SD
s
8 -r
F;
;;f
00 z
CONJRACEPJlON
. 0
OCTOBER 1989 VOL. 40 NO. 4
Vd (1) VI (1) AUCO-a‘ x10' K12 K21 KIO
(mglml) bath) Wfh) Q(h) Cl(Vh)
Tmax (h) CIIMX
;xw
AxlO" B Ka
Parameter
0.7 1.0 15.6 3.3 74 15.2 15.3
0.40 0.15 0.21
0.31 0.09 0.05
0.53 0.12 0.17
10.5 525 0.99 0.72 4.4 1.3 1.53
4.6 456 0.75 0.44 1.1 2.5 1.26
0.9 1.6 64.4 1.1 100 20.3 46.4
3
2
0.6 0.9 27.6 3.7 149 22.1 13.3
7.2 279 1.10 0.79 2.5 1.2 1.04
1
0.12 0.09 0.07
1.9 2.7 27.5 2.1 65 30.1 23.4
3.6 506 0.37 0.25 2.5 4.6 0.65
4
0.56 0.09 0.14
0.59 0.11 0.15
0.6 0.6 33.5 2.1 100 13.4 24.2
14.1 426 1.99 0.63 2.1 1.1 1.66
12.7 405 1.06 0.77 1.6 1.2 1.65 0.6 0.9 42.7 1.7 105 12.4 29.3
6
5
0.16 0.11 0.17
0.57 0.12 0.22
0.19 0.07 0.15
1.1 1.6 26.1 3.1 116 20.2 16.3
5.6 293 0.63 0.36 2.6 2.2 1.21
4.7 440 0.64 0.39 4.6 2.2 1.13 1.1 1.6 14.3 3.6 79 22.4 13.1
9
6
0.6 0.6 23.6 3.5 121 16.1 14.1
12.3 326 1.14 0.66 2.9 1.1 1.36
7
0.9 1.5 25.2 2.4 66 17.3 20.6 0.24 0.09 0.14
0.42 0.12 0.27
5.7 429 0.76 0.44 2.7 2.4 1.46
11
0.7 0.9 16.1 6.6 154 24.6 7.5
7.6 232 1.01 0.77 4.3 1.2 0.91
10
0.26 0.12 0.11
0.9 1.5 22.6 3.1 101 27.1 16.1
3.6 415 0.75 0.46 3.1 2.5 0.95
12
0.36 0.11 0.15
0.9 1.4 26.3 3.0 106 29.1 29.0
7.7 395 0.66 0.59 2.9 2.0 1.27
MearI
0.17 0.02 0.06
0.4 0.6 13.6 1.4 25 5.5 10.2
3.7 92 0.24 0.22 1.1 1.1 0.32
SD
T
TABLE II PHARMACOKINETIC PARAMETERS FOR RU 486 AFTER ORAL ADMINISTRATION OF A 60 MG DOSE ( V?: VOLUME OF CENTRAL COMPARTMENT; FOR OTHER ABBREVIATIONS SEE TEXT. )
CONTRACEPTION
half-life of value for the also had a high subject Omitting the values from subject 4, distribution (tL,a). not marked, with most variability was inter-subject two-fold range. However, showing only a parameters (area under plasma bioavailability as assessed by AUC concentration-time curve), and plasma clearance (C) showed a Tmax and U-;a showed the largest much greater variability. inter-subject variability. Values for the apparent volume of distribution (Vd) suggest that, although some binding such as to were Values occurred, RU 486 was not extensively bound in blood. for clearance were low, showing that elimination of RU 486 from the circulation was slow, which accounts for the long elimination half-life (t$p) and low value for the elimination rate constant (KlO). There mass index and tt2p and significant
were no significant correlations between body and t%P, Cmax, Vd, Cl and AUC, or between Cmax AUC; but the correlation between AUC and Cl was (pcO.01). Discussion
A number of studies on the pharmacokinetics of RU 486 has already been published (8-15), but in view of clinical studies in progress with this compound in Chinese women of (16), it seemed important to study the pharmacokinetics RU 486 in this population. It is difficult to compare the various studies because of the different doses of RU 486 which have been used, the different methods employed for the estimation of serum or plasma RU 486 concentrations, and the number of subjects enrolled in small the studies. Radioimmunoassay methods tend not to be as specific as HPLC due to cross-reaction with metabolites of RU 486 but in one study (10) there was a good correlation between the two methods. Some relevant results from previous single-dose studies are compared with our data in Table III. There is reasonable agreement between the different values for the maximum concentrations (Cmax) achieved in spite of the various doses used. Also, all studies show that the time required (Tmax) to achieve Cmax is low, indicating rapid absorption of the dose. As shown in Table II, the mean value for the half-life of absorption (t%a) was less than 1 h. Distribution was also rapid, the mean half-life of distribution being 1.4 h, but elimination was slow. Serum concentrations were still high 24 h after dosing, and in a number of studies, measurable amounts of RU 486 were detectable in serum for more than 5 days, although in our study, concentrations were very low in the final samples taken at 3 days. These findings reflect the long t%2p of RU 486, the mean value from the studies in Table II (excluding
OCTOBER 1989 VOL. 40 NO. 4
HPLC
Presen
12
15
-
4ikg
14
HPLC
50
3
50
13
ARA
HPLC
11
25lkg
RRA
4
11
to/kg
12
HPLC
200
5
100
IO.11
RIA
RIA
2
50
9
RIA
Method
6
3
100
No. 01
subjed
Dose
ow)
8
Ref.
1
1.7-2.5
1.3io.3
4.9i1.2
2.Okl .I
1
1.5
3.1&1.9
7.5k2.9
3.9kO.4
2.5kl.O
16-36
0.2-0.8
0.2iO.l
1.8&4
19.227.0
0.3iO.l
28.3k13.8
29.1&3
53.76.9
20.6i7.7 0.2iO.l
>27
24
l-2
23.7k3.0
0.520.1
(mg/mb
C24h
0.7*0.1
(h)
Tmax
5.2k1.8
1.9io.4
1.e*o.r
m&w
Cmax
TABLE III PHARMACOKINETIC STUDIES WITH RU 486 (RRA: RADIORECEPTOR ASSAY; RIA: RADIOIMMUNOASSAY; C24H: SERUM CONCENTRATION AT 24 HI
CONTRACEPTION
The longer value ref. 14) being approximately 25 h. reported in ref. 14 may be due to use of a non-specific assay which may have included metabolites of RU 486. As in our study, two other studies (8,13) found that their analytical data fitted a two-compartment open model for pharmacokinetic analysis, whereas Liu et al. (14) used Values analysis. for various non-compartmental pharmacokinetic parameters derived from our data are shown in Table II. Only two other studies have derived any Values for clearance were pharmacokinetic parameters. reported as approximately 1.4 l/h (8) and 1.0 l/h (14) compared to our mean value of 3.0 l/h. Our value for the apparent volume of distribution Vd (106 1) agrees with the value of 90 1 reported by Liu et al. (14). Values for Vd are not so low as to suggest tight binding to serum proteins. Studies (8,12,17) have shown more than 95% of RU 486 in serum to be bound, but there is controversy about the binding protein. Some (8,12) have suggested albumin, whereas others (17) postulate al-acid glycoprotein. Binding of RU 486 to either of these proteins is unlikely to be high affinity, and it is possible that when higher doses of RU 486 are used the acid glycoprotein becomes saturated and albumin then becomes the major binding protein. The values for Vd, therefore, might suggest tight binding of RU 486 to tissue proteins. This would be substantiated by (i) the low clearance and long half-life of elimination of RU 486 and (ii) the higher value for K12 than for K21, suggesting that transfer from the central to a peripheral compartment was more rapid than the reverse. The long half-life and low clearance are unlikely to be due to difficulty in metabolizing RU 486 since metabolites of the compound reach peak concentrations in serum within l-2 h (11). The comparison of our data with that of others (Table III) suggests that the pharmacokinetics of RU 486 in Chinese women do not differ from those of other populations. Acknowledgements This investigation received financial support from the World Health Organization's special Programme for Research, Development and Research Training in Human Reproduction. Ru 486 was kindly provided by Roussel-Uclaf, Paris, France.
OCTOBER 1989 VOL. 40 NO. 4
CONTRACEPTION
References 1.
Baulieu EE. RU 486: an antiprogestin steroid with contragestive activity in women. In: Baulieu EE, Segal eds. The antiprogestin steroid RU 486 and human SJ, fertility control. New York: Plenum Press, 1985;1-25.
2.
Herrmann W, Wyss R, Riondel A, et al. Effet d'un steroide anti-progest&rone chez la femme: interruption du Cycle menstruel et de la grossesse au debut. CR Acad Sci (Paris) 1982;294:933-8.
3.
Termination of very Kovacs L, Sas M, Resch BA, et al. early pregnancy by RU 486 - an antiprogestational Contraception 1984;29:399-410. compound.
4.
Brenner PF, et al. Mishell DR Jr, Shoupe D, Termination of early gestation with the anti-progestin Contraception steroid RU 486: medium versus low dose. 1987;35:307-21.
5.
Early pregnancy termination Birgerson L, Odlind V. with antiprogestins: a comparative clinical study of RU Fertil 486 given in two dose regimens and Epostane. Steril 1987;48:565-70.
6.
Van Look PFA, Bygdeman M. Antiprogestational steroids: a new dimension in human fertility regulation. In: Oxford Reviews of Reproductive Milligan SR, ed. Press, Vol. 11. oxford: Oxford University Biology, 1989; in press.
7.
High performance liquid Ye 2, Zhang G, Bai X. 486 in human determination of RU chromatographic Chin J Chromatogr 1987;3:179-82. plasma.
8.
Busigny M, et al. BOnnat C, Deraedt R, Phannacokinetics of RU 486. In: Baulieu EE, Segal SJ, steroid RU 486 and human eds. The antiprogestin New York: Plenum Press, 1985;103fertility control. 22.
9.
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 New York: Plenum Press, 1985;249-58. control.
10.
H, Shoupe D, Croxatto M, Heikinheimo 0, Tevilin Quantitation of RU 486 in human plasma Ghteenm3ki P. column chromatography. HPLC RIA after and by Contraception 1986;34:613-24.
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CONTRACEPTION
11.
Heikinheimo 0, Kontula K, Croxatto H, Spitz I, Luukkainen T, L;ihteenmskiP. Plasma concentrations and receptor binding of RU 486 and its metabolites in humans. J Steroid Biochem 1987;26:279-84.
12.
Kawai S, Nieman LK, Brandon DD, Udelsman R, Loriaux DL, Chrousos GP. Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man. J Pharmacol Exp Ther 1987;241:401-6.
13.
Lghteenmski P, Heikinheimo 0, Croxatto H, et al. Pharmacokinetics and metabolism of RU 486. J Steroid Biochem 1987;27:859-63.
14.
Pharmacodynamics of the Liu JH, Garzo VG, yen SSC. after oral RU486 in women antiprogesterone administration. Fertil Steril 1988;50:245-9.
15.
antiPharmacokinetics of the Heikinheimo 0. progesterone RU 486 in women during multiple dose administration. J Steroid Biochem 1989;32:21-5.
16.
Gao J, Qiao G-M, Wu Y-M, et al.
17.
Heikinheimo 0, Lshteenmgki PLA, Koivunen E, et al. Metabolism and serum binding of RU 486 in women after various single doses. Hum Reprod 1987;2:379-85.
Pregnancy interruption 486 in combination with dl-15-methylwith RU ~i;;;;z:;~;;; F&8q;;hz;5e;:er: the Chinese experience.
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