CONTRACEPTION
BIOAVAILABILITY AND PHARMACOKINETICS OF NORETHISTERONE ORAL DOSES OF ETHYNODIOL DIACETATE
IN WOMEN AFTER
C. W. Vose*, J. K. Butler, B. M. Williams, J. E. H. Stafford, J. R. Shelton, D. A. Rose, and R. F. Palmer.
G. D. Searle & Company Limited, Lane End Road, High Wycombe, Bucks, HPI2 4HL, England A. M. Breckenridge, M. L ' E. Orme and M. J. Serlin,
Department of Pharmacology and Therapeutics, The University of Liverpool, The Medical Building, Ashton Street, Liverpool L69 3BX, England
ABSTRACT Measurement by radioimmunoassay of plasma norethisterone (NE) has been used to compare the bioavailability of tablets containing ethynodiol diacetate (EDA) with that of a standard oral solution of this progestogen in 12 normal women. The tablets investigated were from three batches which showed different in vitro dissolution rates. There were no significant differences in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak blood levels of NE were reached within 4h of EDA administration in solution or tablets. After the peak, NE plasma levels declined in two phases, with a mean terminal elimination half l i v ~ o f 4 to 6.9h. The pharmacokinetics of NE after EDA administration showed some similarity to those observed by other workers after oral doses of NE itself.
Accepted
for
publication
*All correspondence
January
3,
1979
to this author.
FEBRUARY 1979 VOL. 19 NO. 2
119
CONTRACEPTION
INTRODUCTION Ethynodiol diacetate (EDA; 38,178-diacetoxy-19-nor-17=-pregn-4-en-20-yne) is a synthetic progestogen used in combination with ethinyl oestradiol (EE) or mestranol in a number of oral contraceptive products. Orally administered EDA is rapidly metabolised in man and only its metabolites are found in plasma and urine [ i , ~ . There was no evidence for the presence of the administered compound, which appeared to be deacetylated and oxidised to norethisterone ( N E ; 19-nor-17=-pregn-4-en-20-yn3-one-178-oi). NE, which appears to be the biologically important plasma metabolite [I], is further metabolised to a number of conjugated tetrahydro compounds, which are excreted in urine [2]. The absence of administered drug in biological fluids has hindered attempts to obtain information on the bioavailability of EDA from oral contraceptive formulations. However, a recent study indicated that measurement of plasma concentrations of NE produced by metabolism of EDA. would be of use in assessing the bioavailability of this progestogen [3]. The present report describes the application of this method to a study of the comparative bioavailability of Ovulen 50 R formulations containing EDA (i mg) and EE (0.05 mg). MATERIALS AND METHODS Ovulen 50 tablets from two batches of the standard formulation (treatments A & B) and from an experimental formulation (treatment D) with EDA dissolution rates of 82.6%, 94.6% and 99% at 3h~respectivel~were obtained from Pharmaceutical Development, G. D. Searle, High Wycombe. A solution containing EDA (0.5 mg/ml) and EE (0.025 mg/ml) in ethanol was prepared by Pharmaceutical Development, G. D. Searle, High Wycombe. The oral solution dose (treatment C) was prepared by diluting 2 ml of this ethanolic solution with distilled water (30 ml) innnediately before dosage. Subjects These were 12 normal women (52.3 kg to 75 kg) aged 21 to 37 years, who were judged healthy by a pre-study medical examination, and a biochemical, haematological and urinary screen. These women had given written informed consent to participate in the study. They were having regular menses and had not taken oral contraceptives during the previous 3 months. Clinical Procedure Each subject took her first and third medication within 6 days of cessation of menstruation, and her second and fourth one week later.
120
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
The subjects abstained from food and liquids for Ii hours prior to dosage and for a further 4 hours after dosage, except for the ingestion of water (120 ml) i hour before dosage and at the time of dosage. On four separate occasions each subject received one tablet for treatment A, B or D or the oral solution (treatment C), each of which contained i mg EDA and 0.05 mg EE, according to a balanced crossover study design in which the subjects were randomly allocated to the treatment sequences. Each tablet dose was taken with 120 ml water and the solution dose was followed by 88 ml of water, which had been used to rinse the dosing solution container. Blood samples (i0 ml) were obtained by venepuncture immediately before dosage and at 30, 60 and 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after each dosage. The blood samples were transferred to polystyrene tubes containing lithium heparin and immediately centrifuged. The separated plasma was stored frozen at -18°C until analysed. Measurement of Plasma Norethisterone Concentrations The concentrations of norethisterone in plasma were determined using a modification of the radioimmunoassay method described by Walls et al.[3]. This modification involved establishing the assay method accordlng t-"-'----o~t~e procedure reported by Seaton et al. [4] to allow, computer analysis, of the radioinenunoassay data to ~ n the norethlsterone concentratlons. This modification required the use of the norethisterone antiserum at a final dilution of i in i00,0OO, and analysis of the plasma extract undiluted and at I in 5 dilution. Pharmacokinetic and Statistical Analysis The norethisterone plasma concentrations were analysed by Metzler's NONLIN program [5] to determine the kinetics of appearance and elimination of norethisterone from plasma. The areas under the plasma concentration time curves (AUCo_24) were calculated by the trapezoidal rule. Analysis of variance was used to compare the AUCo-24, time to peak, and peak concentrations of norethisterone for each formulation, after isolation of the between-subjects and between-phases variation. Overall significant differences between the four treatments in the analysis of variance were further investigated by the Newman-Keuls (Studentized Range) multiple comparison test to determine the source of the significance. RESULTS The dissolution profiles of EDA from the Ovulen 50 tablets are shown in Figure i. Treatments B and D showed a faster rate of dissolution and a higher total dissolution at 3 h than treatment A.
FEBRUARY 1979 VOL. 19 NO. 2
121
CONTRACEPTION
r 80!
__.% J ./"
60,
O
l! 40,
•
Treatment D
Q
Treatment B Treatment A
¢m
11
N
20,
Time (min)
45 Figure I.
122
8%
1i0
1~0
In v i t r o dissolution p r o f i l e s of ethynodiol diacetate from d i f f e r e n t Ovulen 50 tablet formulations.
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
TABLE r .
Mean plasma levels of NE (ng/ml mean , S.D.) in 12 normal women afteradmln!stratlon of slngle oral doses of dlfferen.t, forn*u,la,t£ons containing EDA
Time after dosing (h)
T ~ N T A
B
C
D
0.5
0.3±0.5
1.9±1.6
6.9±3.8
2.6±2.6
i
2.7±2.7
4.7±3.8
7.6±3.4
5.9±4.0
1.5
3.5±3.1
5.4±3.0
7.3±3.4
6.9±3.1
2
3.9±2.7
5.6±2.0
7.0±2.3
6.7±2.1
3
4.7±2.0
5.3±1.6
4.3±1.7
5.1±1.7
4
4.4±1.5
4.1±1.5
3.1±1.4
3.7±1.3
6
2.6±0.8
2.6±1.2
1.9±0.8
2.0±0.9
8
2.0±1.0
1.9±1.1
1.4±0.6
1.5±0.5
12
1.0±0.4
1.O±0.5
0.9±0.5
1.0±0.7
24
0.3±0.1
0.3±0.3
0.2±0.3
0.3±0.2
FEBRUARY 1979 VOL. 19 NO. 2
123
CONTRACEPTION
o
•M
¢~
0
-~
~
R
~'~
o
4.-I
.,.4
0
"
0
o
~
÷'
÷'
•
•
°
•
°
°
•
.
°
+1
~
÷'
~
f4
~,
~
~,
~
~
+1
+I
+1
~
•
124
~
~
~
,-
,-~
,
.~
o
,.~"
"~
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
The mean plasma NE concentrations and the derived pharmacokinetic data obtained following oral administration of each EDA treatment are listed in Tables I andll,respectively. Following the administration of treatment A, peak NE levels averaging 6.5 ± 1.9 ng/ml, were reached in i to 4.2 h after dosing. Peak NE levels averaged 7.4 ± 2.4 ng/ml after treatment B and were reached in a similar time period. The oral solution (Treatment C) gave peak plasma concentrations of NE, averaging 8.7 ± 3.3 ng/ml, within 2 h of dosing in most subjects, while treatment D gave peak NE plasma levels (average 8.4 ± 2.8 ng/ml) some 1 to 3 h after dosing. A comparison of the AUCo_24 (Table ll) for the tablet formulations (Treatments A, B and D) and the oral solution (Treatment C) gave the comparative bioavailability data shown in Tablelll. Analysis of variance showed that there were no statistically significant differences in the bioavailability of NE from these formulations, although Treatment A gave a significantly lower and later peak NE level than the solution dose (Treatment C) and a significantly lower peak level than the experimental formulation (Treatment D). TABLEIII. Comparative bioavailability of NE from different formulations containing EDA Treatment
A B D
Availability (95% confidence limits) relative to the oral solution (Treatment C) 0.93 (0.81 - 1.O6) 1.O4 (O.91 - 1.18) 0.99 (0.87 - 1.13)
The plasma concentration data indicated a fairly rapid appearance of NE in plasma after oral administration of EDA, with a shorter appearance half life (TableIl) following administration of the oral solution. Plasma levels of NE appeared to decrease bi-exponentially after the peak with an initial half life of 0.63 ± 0.37 to 1.58 ± 1.O5 h for the different formulations, and a longer elimination half life of 4.O1~ 1.38 to 6.94 ± 3.40 h (Table II). DISCUSSION A comparison of the norethisterone AUCo 24 for the higher dissolution (Treatment B, 94.6% dissolved in 3h), lower dissolution (Treatment A,82.6% dissolved in 3 h) and experimental formulation (Treatment D, 99% dissolved in 3 h) Ovulen 50 tablets with that of the solution formulation (Treatment C) showed that these tablets were essentially bioequivalent to the solution (Table III). Thus, in vitro dissolution rate differences of the order seen for these tablets appear to have little or no in vivo significance. The only significant difference between the formulations was the lower and later peak concentration of norethisterone observed for the lower dissolution rate tablet (Treatment A) compared to the solution.
FEBRUARY 1979 VOL. 19 NO. 2
125
CONTRACEPTION
The rapid rise in plasma NE levels after the oral doses of EDA in solution or in tablets presumably reflects the rapid absorption and metabolism of this progestogen reported by other workers [1,6]. The times to peak plasma concentration of NE after the tablets observed in the present study are similar to those of 1.5 to 3h reported previously after oral EDA administration I~ I and those of 0.5 to 4h reported for NE in women by Okerholm et el, and Back et al.[8] after oral administration of NE. Similarly, both these groups have reported a hi-phasic disappearance of orally administered NE from plasma after the peak plasma concentration, as was seen in the present study following EDA administration. The halflives of these phases observed for NE after oral administration of EDA (Table ll) are similar to those of 1.17 (range 0.41 to 2.6) h and 7.6 (range 4.8 to 12.8) h for the initial and terminal elimination phasess respectively, described by Back et ~i.[8] for orally administered NE in women. Okerholm et a L [7] reported slmilar terminal elimination halflives (4.9 to 6.9 h) for oral NE in women during a bioavailability study. Thus, the pharmacokinetics of NE formed from orally administered EDA are essentially comparable with those seen for NE itself. This appears to be in agreement with the observations of the rapid metabolism of EDA in man [I]. The present study has, therefore, shown the bioequivalence of three batches of Ovulen 50 tablets to an oral solution containing EDA, based on a comparison of plasma levels of NE. In addition it has provided new information about the pharmacokinetics of NE in women after oral administration of EDA, and shown that small variations in in vitro dissolution rates do not affect the bioavailability of NE from tablets containing EDA. Acknowledgements We are indebted to Mr. R. C. Pigott and Dr. V. T. Rice for the dissolution data, to Mr. F. St. John-Forbes for the preparation of the oral solution and to Mrs. M. Porteous and Mrs. M. Rogers for assistance with the clinical part of the study. References I.
Cook, C. E., Karim, A., Forth, J., Wall, M. E., Ranney, R. E., and Bressler, R. C. Ethynodiol diacetate metabolites in human plasma. J. Pharmacol. Exp. Ther. 185: 696-702, 1973.
2.
Kishimoto, Y., Kraychy, S., Ranney, R. E., and Gantt, C. L. Metabolism of oral contraceptives I. Metabolism of ethyndiol diacetate in women. Xenobiotica 2: 237-252, 1972.
3.
Walls, C., Vose, C. W., Horth, C. E. and Palmer, R. F. Radioimmunoassay of plasma norethisterone after ethynodiol diacetate administration. J. Steroid Biochem. 8: 167-171, 1977.
4.
Seaton, B., Lusty, J. and Watson J. A practical model for steroid hormone radioi~unoassays. J. Steroid Biochem. 7: 511-516, 1976.
126
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
5.
Metzler, C. M., NONLIN Upjohn Co., Kalamazoo.
Technical report No. 7292/69/7293/005,
6.
Ishihara, M., Osawa, Y., Kirdani, R. Y. and Sandberg, A. A. Metabolic fate of ethynodiol diace~ate in the baboon. Steroids, 25; 829-847, 1975.
7.
Okerholm, R. A., Peterson, F. E., Keeley, F. J., Smith, T. C. and Glazko, A. J. Bioavailability of norethindrone in human subjects. Europ. J. Clin. Pharmacol. 13; 35-40, 1978.
8.
Back, D. J., Breckenridge, A. M., Crawford, F. E. , Mclver, M., Orme M. L'E., Rowe, P. H. and Smith, E. Pharmacokinetics of norethindrone in women. 2. Single dose pharmacokinetics. Clin. Pharmac. Ther. in press, 1978.
FEBRUARY 1979 VOL. 19 NO.2
127
BIOAVAILABILITY AND PHARMACOKINETICS OF NORETHISTERONE ORAL DOSES OF ETHYNODIOL DIACETATE
IN WOMEN AFTER
C. W. Vose*, J. K. Butler, B. M. Williams, J. E. H. Stafford, J. R. Shelton, D. A. Rose, and R. F. Palmer.
G. D. Searle & Company Limited, Lane End Road, High Wycombe, Bucks, HPI2 4HL, England A. M. Breckenridge, M. L ' E. Orme and M. J. Serlin,
Department of Pharmacology and Therapeutics, The University of Liverpool, The Medical Building, Ashton Street, Liverpool L69 3BX, England
ABSTRACT Measurement by radioimmunoassay of plasma norethisterone (NE) has been used to compare the bioavailability of tablets containing ethynodiol diacetate (EDA) with that of a standard oral solution of this progestogen in 12 normal women. The tablets investigated were from three batches which showed different in vitro dissolution rates. There were no significant differences in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak blood levels of NE were reached within 4h of EDA administration in solution or tablets. After the peak, NE plasma levels declined in two phases, with a mean terminal elimination half l i v ~ o f 4 to 6.9h. The pharmacokinetics of NE after EDA administration showed some similarity to those observed by other workers after oral doses of NE itself.
Accepted
for
publication
*All correspondence
January
3,
1979
to this author.
FEBRUARY 1979 VOL. 19 NO. 2
119
CONTRACEPTION
INTRODUCTION Ethynodiol diacetate (EDA; 38,178-diacetoxy-19-nor-17=-pregn-4-en-20-yne) is a synthetic progestogen used in combination with ethinyl oestradiol (EE) or mestranol in a number of oral contraceptive products. Orally administered EDA is rapidly metabolised in man and only its metabolites are found in plasma and urine [ i , ~ . There was no evidence for the presence of the administered compound, which appeared to be deacetylated and oxidised to norethisterone ( N E ; 19-nor-17=-pregn-4-en-20-yn3-one-178-oi). NE, which appears to be the biologically important plasma metabolite [I], is further metabolised to a number of conjugated tetrahydro compounds, which are excreted in urine [2]. The absence of administered drug in biological fluids has hindered attempts to obtain information on the bioavailability of EDA from oral contraceptive formulations. However, a recent study indicated that measurement of plasma concentrations of NE produced by metabolism of EDA. would be of use in assessing the bioavailability of this progestogen [3]. The present report describes the application of this method to a study of the comparative bioavailability of Ovulen 50 R formulations containing EDA (i mg) and EE (0.05 mg). MATERIALS AND METHODS Ovulen 50 tablets from two batches of the standard formulation (treatments A & B) and from an experimental formulation (treatment D) with EDA dissolution rates of 82.6%, 94.6% and 99% at 3h~respectivel~were obtained from Pharmaceutical Development, G. D. Searle, High Wycombe. A solution containing EDA (0.5 mg/ml) and EE (0.025 mg/ml) in ethanol was prepared by Pharmaceutical Development, G. D. Searle, High Wycombe. The oral solution dose (treatment C) was prepared by diluting 2 ml of this ethanolic solution with distilled water (30 ml) innnediately before dosage. Subjects These were 12 normal women (52.3 kg to 75 kg) aged 21 to 37 years, who were judged healthy by a pre-study medical examination, and a biochemical, haematological and urinary screen. These women had given written informed consent to participate in the study. They were having regular menses and had not taken oral contraceptives during the previous 3 months. Clinical Procedure Each subject took her first and third medication within 6 days of cessation of menstruation, and her second and fourth one week later.
120
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
The subjects abstained from food and liquids for Ii hours prior to dosage and for a further 4 hours after dosage, except for the ingestion of water (120 ml) i hour before dosage and at the time of dosage. On four separate occasions each subject received one tablet for treatment A, B or D or the oral solution (treatment C), each of which contained i mg EDA and 0.05 mg EE, according to a balanced crossover study design in which the subjects were randomly allocated to the treatment sequences. Each tablet dose was taken with 120 ml water and the solution dose was followed by 88 ml of water, which had been used to rinse the dosing solution container. Blood samples (i0 ml) were obtained by venepuncture immediately before dosage and at 30, 60 and 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after each dosage. The blood samples were transferred to polystyrene tubes containing lithium heparin and immediately centrifuged. The separated plasma was stored frozen at -18°C until analysed. Measurement of Plasma Norethisterone Concentrations The concentrations of norethisterone in plasma were determined using a modification of the radioimmunoassay method described by Walls et al.[3]. This modification involved establishing the assay method accordlng t-"-'----o~t~e procedure reported by Seaton et al. [4] to allow, computer analysis, of the radioinenunoassay data to ~ n the norethlsterone concentratlons. This modification required the use of the norethisterone antiserum at a final dilution of i in i00,0OO, and analysis of the plasma extract undiluted and at I in 5 dilution. Pharmacokinetic and Statistical Analysis The norethisterone plasma concentrations were analysed by Metzler's NONLIN program [5] to determine the kinetics of appearance and elimination of norethisterone from plasma. The areas under the plasma concentration time curves (AUCo_24) were calculated by the trapezoidal rule. Analysis of variance was used to compare the AUCo-24, time to peak, and peak concentrations of norethisterone for each formulation, after isolation of the between-subjects and between-phases variation. Overall significant differences between the four treatments in the analysis of variance were further investigated by the Newman-Keuls (Studentized Range) multiple comparison test to determine the source of the significance. RESULTS The dissolution profiles of EDA from the Ovulen 50 tablets are shown in Figure i. Treatments B and D showed a faster rate of dissolution and a higher total dissolution at 3 h than treatment A.
FEBRUARY 1979 VOL. 19 NO. 2
121
CONTRACEPTION
r 80!
__.% J ./"
60,
O
l! 40,
•
Treatment D
Q
Treatment B Treatment A
¢m
11
N
20,
Time (min)
45 Figure I.
122
8%
1i0
1~0
In v i t r o dissolution p r o f i l e s of ethynodiol diacetate from d i f f e r e n t Ovulen 50 tablet formulations.
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
TABLE r .
Mean plasma levels of NE (ng/ml mean , S.D.) in 12 normal women afteradmln!stratlon of slngle oral doses of dlfferen.t, forn*u,la,t£ons containing EDA
Time after dosing (h)
T ~ N T A
B
C
D
0.5
0.3±0.5
1.9±1.6
6.9±3.8
2.6±2.6
i
2.7±2.7
4.7±3.8
7.6±3.4
5.9±4.0
1.5
3.5±3.1
5.4±3.0
7.3±3.4
6.9±3.1
2
3.9±2.7
5.6±2.0
7.0±2.3
6.7±2.1
3
4.7±2.0
5.3±1.6
4.3±1.7
5.1±1.7
4
4.4±1.5
4.1±1.5
3.1±1.4
3.7±1.3
6
2.6±0.8
2.6±1.2
1.9±0.8
2.0±0.9
8
2.0±1.0
1.9±1.1
1.4±0.6
1.5±0.5
12
1.0±0.4
1.O±0.5
0.9±0.5
1.0±0.7
24
0.3±0.1
0.3±0.3
0.2±0.3
0.3±0.2
FEBRUARY 1979 VOL. 19 NO. 2
123
CONTRACEPTION
o
•M
¢~
0
-~
~
R
~'~
o
4.-I
.,.4
0
"
0
o
~
÷'
÷'
•
•
°
•
°
°
•
.
°
+1
~
÷'
~
f4
~,
~
~,
~
~
+1
+I
+1
~
•
124
~
~
~
,-
,-~
,
.~
o
,.~"
"~
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
The mean plasma NE concentrations and the derived pharmacokinetic data obtained following oral administration of each EDA treatment are listed in Tables I andll,respectively. Following the administration of treatment A, peak NE levels averaging 6.5 ± 1.9 ng/ml, were reached in i to 4.2 h after dosing. Peak NE levels averaged 7.4 ± 2.4 ng/ml after treatment B and were reached in a similar time period. The oral solution (Treatment C) gave peak plasma concentrations of NE, averaging 8.7 ± 3.3 ng/ml, within 2 h of dosing in most subjects, while treatment D gave peak NE plasma levels (average 8.4 ± 2.8 ng/ml) some 1 to 3 h after dosing. A comparison of the AUCo_24 (Table ll) for the tablet formulations (Treatments A, B and D) and the oral solution (Treatment C) gave the comparative bioavailability data shown in Tablelll. Analysis of variance showed that there were no statistically significant differences in the bioavailability of NE from these formulations, although Treatment A gave a significantly lower and later peak NE level than the solution dose (Treatment C) and a significantly lower peak level than the experimental formulation (Treatment D). TABLEIII. Comparative bioavailability of NE from different formulations containing EDA Treatment
A B D
Availability (95% confidence limits) relative to the oral solution (Treatment C) 0.93 (0.81 - 1.O6) 1.O4 (O.91 - 1.18) 0.99 (0.87 - 1.13)
The plasma concentration data indicated a fairly rapid appearance of NE in plasma after oral administration of EDA, with a shorter appearance half life (TableIl) following administration of the oral solution. Plasma levels of NE appeared to decrease bi-exponentially after the peak with an initial half life of 0.63 ± 0.37 to 1.58 ± 1.O5 h for the different formulations, and a longer elimination half life of 4.O1~ 1.38 to 6.94 ± 3.40 h (Table II). DISCUSSION A comparison of the norethisterone AUCo 24 for the higher dissolution (Treatment B, 94.6% dissolved in 3h), lower dissolution (Treatment A,82.6% dissolved in 3 h) and experimental formulation (Treatment D, 99% dissolved in 3 h) Ovulen 50 tablets with that of the solution formulation (Treatment C) showed that these tablets were essentially bioequivalent to the solution (Table III). Thus, in vitro dissolution rate differences of the order seen for these tablets appear to have little or no in vivo significance. The only significant difference between the formulations was the lower and later peak concentration of norethisterone observed for the lower dissolution rate tablet (Treatment A) compared to the solution.
FEBRUARY 1979 VOL. 19 NO. 2
125
CONTRACEPTION
The rapid rise in plasma NE levels after the oral doses of EDA in solution or in tablets presumably reflects the rapid absorption and metabolism of this progestogen reported by other workers [1,6]. The times to peak plasma concentration of NE after the tablets observed in the present study are similar to those of 1.5 to 3h reported previously after oral EDA administration I~ I and those of 0.5 to 4h reported for NE in women by Okerholm et el, and Back et al.[8] after oral administration of NE. Similarly, both these groups have reported a hi-phasic disappearance of orally administered NE from plasma after the peak plasma concentration, as was seen in the present study following EDA administration. The halflives of these phases observed for NE after oral administration of EDA (Table ll) are similar to those of 1.17 (range 0.41 to 2.6) h and 7.6 (range 4.8 to 12.8) h for the initial and terminal elimination phasess respectively, described by Back et ~i.[8] for orally administered NE in women. Okerholm et a L [7] reported slmilar terminal elimination halflives (4.9 to 6.9 h) for oral NE in women during a bioavailability study. Thus, the pharmacokinetics of NE formed from orally administered EDA are essentially comparable with those seen for NE itself. This appears to be in agreement with the observations of the rapid metabolism of EDA in man [I]. The present study has, therefore, shown the bioequivalence of three batches of Ovulen 50 tablets to an oral solution containing EDA, based on a comparison of plasma levels of NE. In addition it has provided new information about the pharmacokinetics of NE in women after oral administration of EDA, and shown that small variations in in vitro dissolution rates do not affect the bioavailability of NE from tablets containing EDA. Acknowledgements We are indebted to Mr. R. C. Pigott and Dr. V. T. Rice for the dissolution data, to Mr. F. St. John-Forbes for the preparation of the oral solution and to Mrs. M. Porteous and Mrs. M. Rogers for assistance with the clinical part of the study. References I.
Cook, C. E., Karim, A., Forth, J., Wall, M. E., Ranney, R. E., and Bressler, R. C. Ethynodiol diacetate metabolites in human plasma. J. Pharmacol. Exp. Ther. 185: 696-702, 1973.
2.
Kishimoto, Y., Kraychy, S., Ranney, R. E., and Gantt, C. L. Metabolism of oral contraceptives I. Metabolism of ethyndiol diacetate in women. Xenobiotica 2: 237-252, 1972.
3.
Walls, C., Vose, C. W., Horth, C. E. and Palmer, R. F. Radioimmunoassay of plasma norethisterone after ethynodiol diacetate administration. J. Steroid Biochem. 8: 167-171, 1977.
4.
Seaton, B., Lusty, J. and Watson J. A practical model for steroid hormone radioi~unoassays. J. Steroid Biochem. 7: 511-516, 1976.
126
FEBRUARY 1979 VOL. 19 NO. 2
CONTRACEPTION
5.
Metzler, C. M., NONLIN Upjohn Co., Kalamazoo.
Technical report No. 7292/69/7293/005,
6.
Ishihara, M., Osawa, Y., Kirdani, R. Y. and Sandberg, A. A. Metabolic fate of ethynodiol diace~ate in the baboon. Steroids, 25; 829-847, 1975.
7.
Okerholm, R. A., Peterson, F. E., Keeley, F. J., Smith, T. C. and Glazko, A. J. Bioavailability of norethindrone in human subjects. Europ. J. Clin. Pharmacol. 13; 35-40, 1978.
8.
Back, D. J., Breckenridge, A. M., Crawford, F. E. , Mclver, M., Orme M. L'E., Rowe, P. H. and Smith, E. Pharmacokinetics of norethindrone in women. 2. Single dose pharmacokinetics. Clin. Pharmac. Ther. in press, 1978.
FEBRUARY 1979 VOL. 19 NO.2
127
