Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in post-menopausal women

333

Maturitas, 12 (1990) 333-343

Elsevier Scientific Publishers Ireland Ltd.

MAT 00588

Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in post-menopausal women A.-R. Aedo”, B.-M. Landgrenb and E. Diczfalusy” ‘Department

of Reproductive Endocrinology and bDepartment of Obstetrics and Gynaecology, Karolinska Institute and Hospital, Stockholm (Sweden)

(Received 8 November

1989; revision received 26 February 1990; accepted 8 March 1990)

The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE,S, 2.5 mg/day) and oestradiol valerate (E,V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 pg/day) were compared in 8 post-menopausal women, using a randomized cross-over design. The end points measured in peripheral plasma included oestrone (E,), oestradiol (E,), oestriol (E,), oestrone sulphate (E,S). oestradiol sulphate (E,S) and oestriol sulphate (ES). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed. The plasma levels of E, were invariably below the detection limit (220 pmol/l). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E,S) following PE,S administration than those recorded after E,V ingestion. The terminal half-lives of the circulating oestrogens measured after PE,S administration did not differ from those found after E,V administration. After 21 days of PE,S administration (in combination with LNG for the the last 10 days), the maximum levels of all the oestrogens (except those of EJ were significantly higher than those seen after the first dose. No such difference was observed after E,V administration. There was no difference between the effects of the two treatment regimens with regard to the E,/ E, ratios, but the E,/E,S ratios were significantly lower after PE,S treatment than after E,V administration. It is concluded that, compared with an equivalent dose of PE,S, daily repeated oral administration of E,V yields consistently lower peripheral plasma levels of E, and its principal metabolites. However, in contrast to PE,S therapy, prolonged administration of E,V does not result in an accumulation of the circulating oestrogens measured. (Key words: Menopause, Oestrogen therapy, Pharmacokinetics,

Metabolism)

Correspondence to: Dr. A.R. Aedo, Department of Reproductive Endocrinology, set, Box 60500, S-10401 Stockholm, Sweden.

0378-5122/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

Karolinska sjuku-

334

Introduction In a previous study, the effect of various peroral oestrogen regimens on peripheral gonadotrophin levels was assessed in post-menopausal women, using a completely randomized cross-over design [l]. The regimen, consisting of piperazinc oestrone sulphate (PE,S) 2.5 mg/day, was found to suppress peripheral immunoreactive follicle-stimulating hormone (FSH) and bioactive luteinizing hormone (LH) levels significantly more than the administration of oestradiol valerate (E,V) 2.0 mg/day. In an attempt to correlate these findings with the absorption and/or metabolism of the oestrogens administered, the levels of oestrone (El), oestradiol (EJ, oestriol (E,) and their sulphates were also assessed [2]. The peripheral oestrogen profiles following the administration of the two regimens were very similar and the only consistent difference appeared to be a significantly higher E, level following ingestion of PE,S [2]. In order to investigate the mechanisms which may be responsible for the differences observed, a more detailed, comparative pharmacokinetic investigation was carried out in the present study, using a randomized cross-over design. Subjects and methods

Subjects Eight post-menopausal women volunteered to participate clinical data on these subjects are given in Table I [3].

in this study. Some

Drugs used and study design The two peroral oestrogen preparations investigated were 2.5 mg PE,S (Abbott, North Chicago, U.S.A.) and 2.0 mg E,V (Schering AG, West Berlin, F.R.G.). The PE,S dose is equimolar to 1.6 mg E, and the E,V dose to 1.6 mg E,. In each case, 28-tablet sequential formulations were prepared, comprising 11 tablets containing the oestrogen alone, followed by 10 tablets in which the oestroTABLE I SOME CLINICAL CHARACTERISTICS OF THE 8 POST-MENOPAUSAL WOMEN PARTICIPATING IN THIS STUDY

WI BG TE OG EK BB MA-L SE

Age (Yea@

Weight (kg)

Height (cm)

Years since last MP

Obesity index’

53 61 55 51 53 59 60 57

64 86 73 56 56 67 53 60

172 168 168 156 169 152 157 163

3 9 8 2 1 6 7 11

0.2163 0.3047 0.2586 0.2301 0.1961 0.2899 0.2150 0.2258

‘
335

gen component was combined with 250 pg levonorgestrel (LNG) (Schering AG, West Berlin, F.R.G.) and finally by 7 placebo tablets. The two regimens were administered to each volunteer in a randomized cross-over fashion. Each treatment was administered for a period of 2 x 28 days. The first 28-day period of each treatment represented an adjustment phase (priming), during which no blood samples were taken and the subsequent 28 days constituted a sampling period. A shift was then made to the other regimen, the third 28-day period of medication once again representing an adjustment phase and the fourth such period a sampling phase. During each sampling period, 10 ml heparinized blood samples were drawn as follows. On day 1, immediately before the ingestion of the first tablet, a blood sample was taken and further samples were then drawn after 0.5, 1, 2, 4, 6 and 12 h. On day 21, following the ingestion of the last tablet containing the oestrogenLNG combination, blood samples were drawn after 0.5, 1, 2, 4, 6, 12, 24, 36, 48 and 60 h. Assays The levels of E,, E,, E,, E,S, E,S and E,S were analyzed by the chromatographic radioimmunoassay method described in detail previously [2]. The levels of LNG were assayed by the method of Kanluan et al. [4] and those of SHBG according to the technique described by Cekan et al. [5]. Calculations The levels of the different oestrogens logarithms and their relationship to time [6] for each subject. From the slope (b) constants (K = - 2.303 x b) and the were calculated. The area under the curve according to the following equation: AUC = AU&

analyzed were converted into common was subjected to a regression analysis of the regression lines the elimination elimination half-lives (t,,Z = 0.693/K) (AUC) was calculated for each subject

+ C,/K

where AUC, _ , was computed according to the trapezoid rule [7] and C, was the last measurable concentration. The significance of the differences between areas and between half-lives was assessed using a paired t-test. Ethical aspects An informed consent form was signed by all volunteers after the objectives of the study had been carefully explained to them. It was pointed out in particular that they were free to withdraw from the study at any time. Permission to conduct the study was granted by the Karolinska Hospital Ethics Committee. Results

The E, levels were invariably below the detection limit (220 pmol/l). The initial appearance curves of E, and E, (day 1) and the terminal disappearance curves of

336

El

Q.25

0.125

0.6

E2 DAY 1

1

nmol/l

1

0.h -

0.2 -

0.1 -

DAY 21

iii!?? 11 ’

v------I

0.05 -

1

0

2

4

6

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6

10

12

I

0

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I

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60 HOURS

LNG

nmolh

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2.5 -

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60

HOURS

Fii. 1. Geometric mean values and 95% confidence limits of the peripheral plasma levels of oestrone (E ) and oestradiol @J in 8 post-menopausal women before and after a single oral dose (day 1) and afkr 21 daily doses (day 21) of piperazine oestrone sulphate (PE,S 2.5 me/day, 0) and ocstradiol valerate (E*V 2.0 mg/day, 0). The last 10 doses of oestrogen were given in combination with levonorgestrel (LNG 2SO &day). The levels of LNG after the last dose (day 21) are also shown.

331

E,, E, and LNG (day 21) are shown in Fig. 1, while the initial appearance and terminal disappearance curves of E,S, E,S and E,S can be seen in Fig. 2. It should be noted that all the appearance curves were obtained in the absence of LNG and all the disappearance curves in its presence. The data indicate that, in general, the administration of PE,S induced consistently higher levels of all the oestrogens than those seen after E,V ingestion. A closer inspection of the data in Fig. 1 reveals that, following the ingestion of the first PE,S tablet, the E, levels rose continuously for 12 h, with a significant positive regression (P < O.OOl), reaching the highest level (228 pmol/l) after 12 h. In contrast, the first dose of E,V appeared to give rise to lower E, levels,

6.25

1.6

r

2.0 1 nmol/

I

DAY

1

1

t

1

1

I

I

,

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1

DAY

,

0

I

I

20

21

I

40

1

60

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Fig. 2. Peripheral plasma levels of oestrone sulphate (E,S) oestradiol sulphate (E,S) and oestriol phate (E,S) in 8 post-menopausal women. For further details see legend to Fig. 1.

sul-

338

the maximum (129 pmol/l) being reached after an hour after which an approximately constant level was maintained for up to 12 h. Comparison of the E,/E, ratios in the peripheral plasma did not reveal any significant difference between the metabolism of PE,S and E,V. However, the E,/E,S ratios were significantly higher following the administration of E,V than after PE,S, both on day 1 (P < 0.001) and on day 21 (P < 0.05). On the other hand, the E,/E,S ratio was higher following PE,S than after E,V on day 1 (P < 0.05), but there was no difference on day 21. Some pharmacokinetic parameters are indicated in Table II. Comparison of the values obtained on day 1 after the initial administration of PE,S and E2V reveals no significant difference in the C_ values; f_ was signifiin the case of the E, and E,S levels. cantly different (P < 0.05) Peak concentration (C_) was significantly higher in the case of E, (P< O.Ol), E,S (P < 0.05) and E,S (P < 0.05)following repeated administration of PE,S (day 21) than after E,V administration. Comparison of the C_ values on days 1 and 21 following PE,S administration revealed significantly higher levels of E, (P < O.OOl), E,S (P < O.OOl), E,S (P < 0.05)and E,S (P < 0.01) on day 21. No such difference was found after the EzV ingestion. Because of the study design (daily pill intake), certain pharmacokinetic parameters could only be calculated after ingestion of the last pill (day 21). These indices are shown in Table III. The AUC was significantly greater after PE,S than after E,V administration in the case of E, (P < O.OOl), E, (P < O.Ol), E,S (P < 0.01) and E,S (P <0.05). There was no significant difference with respect to the AUC in the case of E,S and LNG. The apparent t,,, and K values after PE,S and E,V administration were similar and did not differ significantly from each other. The time required for a 50% reduction in peripheral plasma levels following the administration of the last tablet was longest in the case of E, and E,S (> 30 h) and shortest in that of E,S (< 13 h). Finally, a pharmacodynamic parameter, namely SHBG level, was also assessed because of its known interaction with E, metabolism. As shown in Fig. 3, the SHBG levels observed after PE,S and E,V administration were very similar and showed a significant gradual rise (P < 0.01) between days 1 and 11. It can also be seen that the levels dropped to baseline values when LNG was administered for 10 days in combination with the oestrogens. Discussion

The results presented in this paper in general confirm those of previous comparative pharmacokinetic and pharmacodynamic studies [1,2]. The finding that the AUC for most of the oestrogens investigated (excluding E,S) was significantly greater after PE,S than after E,V administration provides a satisfactory explanation for the previously observed differences in the gonadotrophin-suppressing potency of equimolar quantities of PE,S and E,V [l]. On the other hand, the

4.1 2.5-6.6 5.8 3.3-10 1.0 0.54-1.9

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0.19 0.12-0.19 44.4 36-56 0.60 0.39-0.92 0.19 0.14-0.27 -

.4

PE,S = piperazine oestrone sulphate, E,V = oestradiol valerate. LNG E,S = oestradiol sulphate, E,S = oestriol sulphate.

= levonorgestrel, E, = oestrone, E, = oestradiol, E,S = oestrone sulphate.

Levels of significance: a vs. a: P < 0.001; b vs. b: P < 0.01; c vs. c: P < 0.05; d vs. d: P < 0.001; e vs. e: P < 0.05; f vs. f: P < 0.05; g vs. g: P < 0.01; h vs. h: P< 0.05; i vs. i: P< 0.05.

LNG

E,S

EZS

E,S

6.5 4.3-9.9 3.1 1.4-6.9

0.37 0.24-0.56 96.6”” 61-154

9.8’ 7.2-14 4.4 3.8-5.2

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E,

3.8 3.0-5.0 3.5 2.4-5.1 1.9 1.0-3.7

I.446 0.97-22

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Cmu (Mlol/l)

Day 21

5.2 4.3-6.1

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4.2 2.8-6.3

2.3qb 1.8-3.1

CQIU (nmol/l)

C(nmo1/1) 6.4 4.5-9.2

Day 1

Oestradiol valerate (2.0 mg/day)

Day 21

1.3’ 0.92-1.8

Day 1

Piperazine oestrone sulphate (2.5 m&day)

E,

End point

PEAK CONCENTRATION CC_) AND TIME REQUIRED TO REACH PEAK CONCENTRATION (t_) OF VARIOUS CIRCULATING OESTROGENS FOLLOWING A SINGLE ORAL DOSE (DAY 1) AND REPEATED DOSES (DAY 21) OF PE,S AND E,V. LNG (250 &DAY) WAS ADMINISTERED ON DAYS 1I-21. (GEOMETRIC MEAN VALUES AND 95% CONFIDENCE LIMITS)

TABLE II

36.4 24.1-55.1 12.9 12.1-13.7 19.4 10.7-35.1 34.6 24.848.2

19.76 11.8-33.1 1640 1230-2170 47.9 22.3-100 57.3 30.3-l 10 350 150-840

0.020 0.014-0.029 0.058 0.047-0.072 0.031 0.014-0.066 0.022 0.017-0.029 0.028 0.021-0.039

34.7 24.2-49.7 11.8

9.33-14.8

22.4 10.6-47.9 31.6 24.6-41.1 24.4

17.9-33.3

E*

Levels of significance: a vs. a: P < 0.001; b vs. b: P < 0.01; c vs. c: P < 0.05; d vs. d: P < 0.05. PE,S = piperazine oestrone sulphate, E,V = oestradiol valerate. LNG = levonorgestrel. E, = oestrone, E, = oestradiol, E,S = oestrone sulphate. E*S = oestradiol sulphate, E,S = oestriol sulphate.

LNG

E,S

E*S

21.4 16.8-22.5

39.e 29.6-53.0 12.9 9.00-18.6 94Q 640-1390 26.9d 11.4-63.5 48.4 25.8-90.6 300 140-630 0.037 0.031-0.044 0.014 0.005-0.039 0.054 0.051-0.057 0.036 0.020-0.065 0.020 0.014-0.028 0.032 0.025-0.032 19.9 16.5-23.9

65.9 52.8-82.2

0.037 0.030-0.045

18.5 15.0-22.8

E,

ES

AUC (nmol/l per h)

K (h-l)

K k

Oestradiol valerate (2.0 m&day)

AUC (mnol/l per h)

oestrone sulphate (2.5 mg/day)

(h-l)

Pipertine

k

End point

ELIMINATION HALF-LIVES (t,,J, ELIMINATION RATE CONSTANTS (K) AND AREAS UNDER THE CURVE (AUC) FOR VARIOUS CIRCULATING STEROIDS FOLLOWING 21 DAYS OF PE,S AND E,V ADMINISTRATION. DURING THE LAST 10 DAYS OF OESTROGEN ADMINISTRATION LNG (250 pg/DAY) WAS ADDED. (GEOMETRIC MEAN VALUES AND 95% CONFIDENCE LIMITS)

TABLE Ill

341

0

2

L

6

8

IO

21

DAYS

Fig. 3. Geometric mean values and 95% confidence limits for sex-hormone-binding globulin (SHBG) levels during 11 consecutive days of oestrogen administration (0 = piperazine oestrone sulphate, 0 = oestradiol valerate). The equation of the line calculated from both sets of data was: y = 1.59 (0.03) + 0.02 (0.007)x. The values after an additional 10 days of combined treatment with levonorgestrel are also indicated.

present results also establish that - in contradistinction to the effect of PE,S the repeated daily administration of E,V does not result in an accumulation of E, or any of its five circulating metabolites analyzed. These findings confirm and expand the conclusions reached by Dusterberg et al. (81. Hence, on balance, it would appear that the pharmacokinetic properties of orally administered E,V compare favourably with those of PE,S. A significant increase in peripheral E, levels was invariably observed after the administration of both preparations, confirming the results of several previous studies [8-131, with two exceptions [14,15]. The E/E2 ratios in peripheral blood were the same with both preparations. This finding and those presented in Figs. 1 and 2 provide evidence in support of the view that the metabolism of the two esterified oestrogens is qualitatively similar. Furthermore, the E,/E,S ratios were significantly higher after E,V administration than after PE,S ingestion, which seems to suggest that at least some E,S can reach the circulation without being hydrolyzed and is subsequently metabolized elsewhere. This proposition appears to derive some support from the finding that, following intravenous injection of E,S, its conversion to E, and/or E, is relatively limited during transit in the general circulation [la]. The values for the apparent half-life of the terminal disappearance phase of the various oestrogens were similar after the administration of the two preparations. It is of some interest in this respect that the time required for a 50% reduction in peripheral plasma levels was longest for E, and E,S (over 30 h), whereas it was shortest for E,S (less than 13 h). These data seem to underline the important reservoir role played by E,S in the formation of the biologically active oestrogens [2,17,18]. The levels and behaviour of SHBG after the administration of PE,S, E,V and LNG were in agreement with previously reported data [19-211; combination with LNG completely neutralized the effect of oestrogen treatment.

342

The LNG terminal half-life values were by and large in agreement with previously published data [22-251 and seemed to correspond more or less to the gamma t,,, levels reported by Humpel et al. [23]. It is concluded that, in comparison with equivalent doses of PE,S, repeated daily oral administration of E,V produces consistently lower peripheral plasma levels of E, and its principal metabolites. However, in contrast to PE,S therapy, prolonged administration of E,V does not result in accumulation of the circulating oestrogens measured. Acknowledgement The expenses of this investigation were defrayed by a research grant from the Leo Research Foundation, Helsingborg, Sweden. References 1

5 6 7 8 9

10

11

12 13

14 15

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