Kinetics of norethindrone in women II. Single-dose kinetics In order to study the kinetics of norethindrone in women, we have administered single doses of 4 preparations of norethindrone (N) to 6 women (aged 21 to 23) in random order. The preparations were I mg N acetate and SO /Lg ethinylestradiol EE 2) (Minovlar), a dose of I.OS mg N (Noriday), 3 mg N acetate and SO /Lg EE2 (Gynovlar), and an intravenous preparation of I mg N with SO /Lg EE 2. Blood samples were taken at intervals up to 24 hr after dosing and plasma norethindrone concentrations were measured by radioimmunoassay. The plasma concentration decay slope fitted a two-component open model with an initial rapid decay (half life 0.41 to 2.6 hr) followed by a slower beta phase with a half-life of between 4.8 and 12.8 hr. The kinetics of norethindrone were not affected by the concomitant administration of EE 2. The bioavailability of norethindrone after an oral dose of I mg was between 47% and 73% compared with an equivalent intravenous dose. The plasma clearance of norethindrone after I mg N acetate and SO /Lg EE2 was 404.7 ± 31.7 mllkglhr and the apparent volume of .distribution was 4.28 ± 0.S6 Llkg. These values were not significantly different from the figures obtained after administration of 1.0S mg N. After an oral dose of 3 mg N acetate and SO /Lg EE 2, the bioavailability of norethindrone was significantly less (between 32% and 70%) than that after I mg N acetate and SO /Lg EE 2 explaining, at least in part, the lower than expected plasma concentrations of norethindrone in women on long-term treatment with 3 mg N acetate and SO /Lg EE 2.
D. J. Back, Ph.D., A. M. Breckenridge, M.D., Francesca E. Crawford, B.Sc., M. Mciver, M.B., M. L'E. Orme, M.D.,* P. H. Rowe, Ph.D., and Eileen Smith, B.Sc. Liverpool, England Department of Pharmacology and Therapeutics, University of Liverpool
Norethindrone ( 17a -ethinyl- I7(3 - hydroxyestr-4-en-3-one) is a synthetic progestogen which is widely used both on its own and as a component of many combined contraceptive steroid preparations. Despite its widespread
Received for publication June 2, 1978. Accepted for publication July 12, 1978. Reprint requests to: Dr. M. L'E. Orme, Department of Pharmacology and Therapeutics, New Medical Bldg., Ashton St., Liverpool, L69 3BX.
448
use, little is known of the relationship of blood concentrations of norethindrone to efficacy or toxicity. The plasma half-life (tV2) of norethindrone has been variously estimated as between 3 and 5 hrll and about 6 hr9 , or as a biexponential decay with a terminal tV2 ranging between 3 and 12 hr. 6 We have developed a sensitive radioimmunoassay method for the measurement of norethindrone concentrations in plasma. 2 During our initial studies in women taking the combined form of oral contraceptive, we found
0009-9236/78/100448+06$00.60/0 © 1978 The C. V. Mosby Co.
Volume 24 Number 4
that the 12-hr plasma norethindrone concentration during multiple dosing with 1 mg norethindrone acetate and 50 p.,g ethinylestradiol was considerably higher (3.31 ± 0.77 ng/ml) than the 12-hr concentration measured after a single dose (0.58 ± 0.08 ng/ml). We also found that during the first cycle of administration of contraceptive steroids to nulliparous women, the plasma norethindrone concentration rose progressively, due in part to an increase in sex hormone-binding globulin.2 We also found that the mean plasma concentration of norethindrone in women taking 3 mg norethindrone acetate and 50 p.,g ethinylestradiol was only 1.4 times as high as that in women taking I mg norethindrone and 50 p.,g ethinylestradiol In order to explain this discrepancy and to study further the kinetics of norethindrone in women, single-dose studies were performed with 4 different preparations of norethindrone, and these are reported in this paper. Materials and methods
Plan of study. The kinetics of norethindrone after administration of single doses was studied in 6 women between 21 to 23 yr of age who were in good general health. None of the volunteers received any other medication for the duration of the study, and none had previously been taking contraceptive steroids. Each subject received single doses of 4 different preparations of norethindrone in random order. The doses were given in the middle of successive menstrual cycles at 4-wk intervals. The three preparations containing norethindrone (N) given orally were I mg N acetate and 50 p.,g ethinylestradiol (EE 2); 3 mg N acetate and 50 p.,g EE 2; and 350 p.,g N per tablet (Noriday) and which was given in dose of 1.05 mg. These preparations were taken orally after an overnight fast and no food or drink was allowed until 3 hr after dosing. The fourth preparation was an intravenous dose of 1 mg Nand 50 p.,g of EE 2. The intravenous doses were prepared by the G. D. Searle Laboratories when stability and sterility were also tested. The norethindrone for intravenous use was prepared in 5 ml ethyl alcohol: water (50: 50, v: v) and EE2 was prepared in a volume of 5 ml containing 1.5 ml of ethyl alcohol and 3.5 ml water. The intravenous
Norethindrone kinetics in women
449
preparations were diluted to 20 ml in sterile saline and given by slow intravenous infusion from separate syringes over 10 min with the subject supine. No ill effects were experienced during or after drug administration. Blood samples (20 ml) were taken into heparinized tubes through an indwelling intravenous cannula placed in the opposite arm at 0.5, 1.0, 2.0,3.0,4.0,6.0,8.0, 11.0, 14.0, and 24.0 hr after dosing. Additional blood samples were taken after the intravenous dose at 0.25, 0.75, and 1.5 hr after the infusion. Blood samples were centrifuged at 2,000 rpm for 10 min and the supernatant plasma was removed and stored at -25 0 C until analyzed. Plasma concentrations of norethindrone were measured by radioimmunoassav. 2
Calculations. Two-compartment open model analysis. The decline in plasma concentration of norethindrone with respect to time appeared biexponential and the data were therefore analyzed according to a two-compartment open model. 10 The plasma tV2 of norethindrone was calculated from the terminal part of the plasma disposition curve (f3 phase) with the use of a minimum of 4 points in all instances. The value of the rate constant for the initial (n:) disposition phase was calculated by means of residuals. The area under the plasma concentration time curve (AUC) from 0 to 24 hr was calculated by the trapezoidal rule with the use of a programmable pocket calculator (Texas S.R.52). The Aue from 24 hr to infinity was in each case less than 5% of the AUC from 0 to 24 hr. Bioavailability. The bioavailability (F) was calculated for each subject as the ratio between the areas under the oral and intravenous plasma concentration time curves corrected for the dose administered. The oral dose was I mg N acetate and 50 p.,g EE2 (1 mg N acetate === 0.8766 mg N). The results were tested for significance by means of Student's t test. Plasma clearance. Plasma clearance (Cl) was calculated from the equation: Cl =
FD AUC x BW
(I)
where F is the fraction of the dose (D) absorbed
Back et al.
450
Clin. Pharmacol. Ther. October 1978
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Fig. 1. Plasma concentrations of norethindrone after the administration of a single dose of norethindrone (I mg) to 6 subjects by both oral 1 mg N acetate and 50 t.tg EE2 and intravenous routes (mean ± SE).
Fig. 2. Plasma concentrations of norethindrone in Subject C. M. after the administration of 4 different preparations of norethindrone.
into the systemic circulation and BW is body weight.! Apparent volume of distribution.! The apparent volume of distribution (Vd area) was calculated as:
and 12.8 hr (mean, 7.6 hr). There were no significant differences between the values for the {3 phase t1;2 between the 4 preparations, the values being I mg N acetate and 50 /J-g EE 2 , 7.4 ± 0.69 hr (mean ± SE); intravenous dose, 8.0 ± 1.35 hr; 1.05 mg N, 7.7 ± 1.14 hr; and 3 mg N acetate and 50 /J-g EE 2, 7.5 ± 0.94 hr. Bioavailability. The values for the AVC measurements are shown in Table II. Comparison of the values for the intravenous dose (F = I) and the I mg N acetate and 50 /J-g EE2 preparation shows that norethindrone is not completely bioavailable. The mean value for F is 0.64 with a range of 0.47 to 0.73. There was no significant difference between the AVC value for 1.05 mg Nand 1 mg N acetate and 50 /J-g EE 2 • However, the AVC after 3 mg N acetate and 50 /J-g EE 2, when corrected for dosage, is less than that for 1 mg N acetate and 50 /J-g EE2 (0.52 ± 0.06 compared with 0.64 ± 0.04 P < 0.05). Expressed as a ratio, the norethindrone AVC 3 mg N acetate and 50 /J-g EE 2: I mg N acetate and 50 /J-g EE2 is 2.4: 1, although the dose ratio is 3: 1. Plasma clearance and apparent volumes of
VD area = CI/{3
(2)
where {3 is the rate constant of the terminal part of the concentration/time curve. Results
Intravenous dosing. Concentrations of norethindrone were measured in the first sample taken IS min after the end of the intravenous infusion and ranged between 12.0 and 29.0 ng/ml. Plasma concentrations decreased rapidly and after 4 to 6 hr a terminal single exponential phase followed (Fig. I). Oral dosing. N was absorbed rapidly after oral dosing, with peak plasma concentrations occurring in all cases by 2 hr and in most cases by I hr (Fig. 2). The values for a and {3 are given in Table I. The t1;2 of the initial (a) phase varied between 0.41 and 2.6 hr (mean, 1.17 hr) and the second ({3) phase t1;2 varied between 4.8
Norethindrone kinetics in women
Volume 24 Number 4
451
Table I. Rate constants of the fast disposition phase ( a) and the slow disposition phase (f3) after the administration of 4 preparations of norethindrone to 6 subjects (hr- I ) 1 mg N acetate and 50 fJ-g EE2 Patient
J.c.
P. C. R. C. M.O. C. M. M.R. Mean ±SE
a
I
a
f3
0.603 0.770 0.420 0.641 0.924 0.660 0.670 ±0.068
Intravenous dose
0.066 0.106 0.108 0.108 0.112 0.095 0.099 ±0.007
0.597 1.690 0.630 0.866 0.693 0.541 0.836 ±0.176
I
1.05 mg N acetate
f3
a
0.054 0.124 0.123 0.133 0.090 0.062 0.098 ±0.014
0.456 0.578 0.936 0.568 1.155 0.330 0.671 ±0.127
I
3 mg N acetate and 50 fJ-g EE2
f3
a
0.065 0.064 0.144 0.089 0.116 0.107 0.097 ±0.013
0.266 0.815 0.654 0.722 0.340 0.693 0.582 ±0.091
1
f3 0.064 0.076 0.126 0.090 0.112 0.117 0.097 ±0.01O
Table II. Areas under the plasma concentration/time curve (AUe) after 4 single doses of norethindrone to 6 normal subjects (hr x ng/ml) 1 mg N acetate and 50 pg EE2 Patient
AUC
I
J. C. 25.4 33.2 P. C. R. C. 32.6 M.O. 29.7 C.M. 37.4 M.R. 27.0 Mean 30.9 ±SE ±0.73 Significance compared with 1 mg N acetate and 50 fJ-g EE2 corrected to I mg dose
F 0.73 0.71 0.68 0.47 0.62 0.63 0.64 ±0.04
Intravenous dose AUC
I
35.0 47.0 47.6 62.6 60.4 42.8 49.2 ±1.76
distribution. The plasma clearances of norethindrone with I mg N acetate and 50 J,Lg EE 2,
1.05 mg N, and the intravenous preparation are shown in Table III. Because of the discrepancy of dose between the oral and intravenous routes, clearances of norethindrone with 3 mg N acetate and 50 J,Lg EE2 were not calculated. The mean plasma clearance of N after I mg N acetate and 50 J,Lg EE2 was 400.0 ± 31.7 ml/kg/hr, and there was no significant difference in the plasma clearance of norethindrone between the other preparations. The mean apparent volume of distribution of norethindrone with I mg N acetate and 50 J,Lg EE2 was 4.28 ± 0.56 Llkg which did not differ significantly after adminis-
F
1.05 mg N acetate AUC
I
29.0 34.9 39.6 22.2 28.3 25.8 29.9 ±1.06 p < 0.005
F 0.83 0.74 0.83 0.35 0.47 0.60 0.64 ±0.08 NS
3 mg N acetate and 50 fJ-g EE2
~UC_ 66.1 74.0 100.6 59.7 74.4 69.9 74.1 ±2.33
J
F -
0.63 0.52 0.70 0.32 0.41 0.54 0.52 ±0.06 P < 0.05
tration of the other preparations of norethindrone (Table I V). Discussion
These studies show that after a single dose, the disposition of norethindrone in plasma follows a biexponential pattern with an initial rapid phase lasting for up to 6 hr after dosing. This is followed by a slower, f3 phase with a tV2 of between 4.8 and 12.8 hr. These figures for the terminal phase tl/2 are in the range reported by other workers. 4, 6, 7, 9, 11 Ethinylestradiol did not alter the plasma tV2, plasma clearance, or apparent volume of distribution of norethindrone when the data following administration of
452
Back et al.
Clin. Pharmacal. Ther. October 1978
m.
Table Plasma clearances of norethindrone after the administration of 3 different preparations of norethindrone to 6 subjects mllkg/hr Patient
1. C. P. C. R. C. M.O. C.M. M.R. Mean ±SE Significance relative to I mg N acetate and 50 JLgEE 2
I mg N acetate and 50 JLg EE2
Intravenous dose
I.05 mg N acetate
427 464 443 319 267 480 400.0 ±31.7
374 407 388 279 260 422 355.0 ±27.9 NS
328 386 320 355 344 441 362.3 ±18.4 NS
Table IV. Apparent volumes of distribution of norethindrone after administration of three preparations of norethindrone to 6 subjects Llkg Patient
J. C. P. C. R. C. M.O. C. M. M.R. Mean ±SE Significance relative to I mg N acetate and 50 JLg EE2
I mg N acetate and 50 JLg EE2
Intravenous dose
I.05 mg N acetate
6.40 4.42 4.09 2.94 2.65 5.05 4.28 ±0.56
6.90 3.29 3.13 2.09 2.89 3.41 3.62 ±0.80 NS
5.01 6.02 2.21 3.99 2.98 4.13 4.06 ±0.56 NS
1.05 mg N (containing no EE 2 ) were compared with the data obtained with other preparations. We have also shown that the bioavailability of norethindrone is significantly less than 100% when given orally, with a mean bioavailability of 64% (range, 47% to 73%) compared with the intravenous formulation. This reduced bioavailability might be due to incomplete absorption but norethindrone is reported to be well absorbed after oral administration. 4 The reduced bioavailability of norethindrone may therefore be due to first-pass metabolism either in the liver or in the gut wall. Our studies do not enable us to differentiate between these two sites but it is known that the gut wall contributes
significantly to the first-pass effect of norethindrone in rats.3 It is of interest that another oral progestogen, levo norgestrel, has recently been shown not to have a first-pass effect in low doses. s The bioavailability of norethindrone after a 3-mg oral dose is significantly reduced, compared with a I mg oral dose of norethindrone with mean values of 52% and 64%, respectively. A similar finding has been demonstrated by Okerholm and associates. 8 Using much larger doses of norethindrone, they showed that the AVe after a single 20-mg oral dose of norethindrone was only twice the AVe after 5 mg norethindrone. In our study the AVe of nor-
Volume 24 Number 4
ethindrone after 3 mg N acetate and 50 p.g EE2 was only 2.4 times as great as that after I mg N acetate and 50 p.g EE 2 • These data are in agreement with the data in the previous paper showing plasma concentrations of norethindrone lower than predicted after multiple dosing with 3 mg N acetate and 50 p.g EE2 (8.3 ± 0.75 ng/ml) compared with I mg N acetate and 50 p.g EE2 (5.9 ± 0.47 ng/ml). We are unable to calculate the plasma clearances or apparent volumes of distribution of norethindrone after a 3-mg oral dose, since no 3-mg intravenous dose was given. A possible explanation is that with a larger single dose of norethindrone, the concentration of the drug in the hepatic portal vein may exceed the binding capacity of the sex hormone-binding globulin. This would lead to a resultant rise in the free concentration of norethindrone in the portal vein and an increased clearance of norethindrone from the plasma by the liver. We would like to thank the Mersey Regional Health Authority, the Wellcome Trust, G. O. Searle Pharmaceuticals, and the Peel Medical Trust for financial assistance. We thank Professor M. Row land for advice on pharmacokinetics.
Norethindrone kinetics in women
3.
4. 5.
6.
7.
8.
9.
References I. Alexandersson B: Pharmacokinetics of desmethylimipramine and nortryptiline in man after single and multiple oral doses-A cross over study. Eur J Clin Pharmacol 5:1-10,1972. 2. Back OJ, Breckenridge AM, Crawford FE, McIver M, Orme ML'E, Rowe PH. Smith E: Kinetics of norethindrone in women. I. Radio-
10.
II.
453
immunoassay and concentrations during multiple dosing. CUN PHARMACOL THER 1978. Back OJ, Breckenridge AM, Crawford FE, Orme ML'E, Rowe PH, Smith E: First-pass effect of norethindrone in rabbits and rats. J Pharmacol Exp Ther (In press.) Fotherby K, Warren RJ: Bioavailability of contraceptive steroids from capsules. Contraception 14:261-267, 1976. Humpel M, Wendt H, Pommerenke G, Weiss Chr, Speck U: Investigations of pharmacokinetics of levo norgestrel to specific considerations of a possible first-pass effect in women. Contraception 17 :207 -220, 1978. Mills TM, Lin TJ, Hemandez-Ayup S, Greenblatt RB, Ellegood 10, Mahesh YB: The metabolic clearance rate and urinary excretion of oral contraceptive drugs. I. Norethindrone. Am J Obstet Gynecol 120:764-772, 1974. Nygren KG, Lindberg P, Martinsson K, Bosu WTK, Johansson EOB: Radioimmunoassay of norethindrone: Peripheral plasma levels after oral administration to humans and rhesus monkeys. Contraception 9:265-278, 1974. Okemolm RA, Peterson FE, Keeley FJ, Smith TC, Glazko AJ: Bioavai!abi!ity of norethindrone in human subjects. Eur J Clin Pharmacol 13: 35-39, 1978. Pasqualini JR, Castellet R, Portois MC, Hill JL, Kincl FA: Plasma concentrations of ethinyloestradiol and norethisterone after oral administration to women. J Reprod Ferti! 49:189-193, 1977. Riegelman S, Loo JCK, Rowland M: Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J Pharm Sci 57: I 17-123, 1968. Warren RJ, Fotherby K: Radioimmunoassay of synthetic progestogens, norethisterone, and norgestrel. J Endocrinol 62:605-618, 1974.
D. J. Back, Ph.D., A. M. Breckenridge, M.D., Francesca E. Crawford, B.Sc., M. Mciver, M.B., M. L'E. Orme, M.D.,* P. H. Rowe, Ph.D., and Eileen Smith, B.Sc. Liverpool, England Department of Pharmacology and Therapeutics, University of Liverpool
Norethindrone ( 17a -ethinyl- I7(3 - hydroxyestr-4-en-3-one) is a synthetic progestogen which is widely used both on its own and as a component of many combined contraceptive steroid preparations. Despite its widespread
Received for publication June 2, 1978. Accepted for publication July 12, 1978. Reprint requests to: Dr. M. L'E. Orme, Department of Pharmacology and Therapeutics, New Medical Bldg., Ashton St., Liverpool, L69 3BX.
448
use, little is known of the relationship of blood concentrations of norethindrone to efficacy or toxicity. The plasma half-life (tV2) of norethindrone has been variously estimated as between 3 and 5 hrll and about 6 hr9 , or as a biexponential decay with a terminal tV2 ranging between 3 and 12 hr. 6 We have developed a sensitive radioimmunoassay method for the measurement of norethindrone concentrations in plasma. 2 During our initial studies in women taking the combined form of oral contraceptive, we found
0009-9236/78/100448+06$00.60/0 © 1978 The C. V. Mosby Co.
Volume 24 Number 4
that the 12-hr plasma norethindrone concentration during multiple dosing with 1 mg norethindrone acetate and 50 p.,g ethinylestradiol was considerably higher (3.31 ± 0.77 ng/ml) than the 12-hr concentration measured after a single dose (0.58 ± 0.08 ng/ml). We also found that during the first cycle of administration of contraceptive steroids to nulliparous women, the plasma norethindrone concentration rose progressively, due in part to an increase in sex hormone-binding globulin.2 We also found that the mean plasma concentration of norethindrone in women taking 3 mg norethindrone acetate and 50 p.,g ethinylestradiol was only 1.4 times as high as that in women taking I mg norethindrone and 50 p.,g ethinylestradiol In order to explain this discrepancy and to study further the kinetics of norethindrone in women, single-dose studies were performed with 4 different preparations of norethindrone, and these are reported in this paper. Materials and methods
Plan of study. The kinetics of norethindrone after administration of single doses was studied in 6 women between 21 to 23 yr of age who were in good general health. None of the volunteers received any other medication for the duration of the study, and none had previously been taking contraceptive steroids. Each subject received single doses of 4 different preparations of norethindrone in random order. The doses were given in the middle of successive menstrual cycles at 4-wk intervals. The three preparations containing norethindrone (N) given orally were I mg N acetate and 50 p.,g ethinylestradiol (EE 2); 3 mg N acetate and 50 p.,g EE 2; and 350 p.,g N per tablet (Noriday) and which was given in dose of 1.05 mg. These preparations were taken orally after an overnight fast and no food or drink was allowed until 3 hr after dosing. The fourth preparation was an intravenous dose of 1 mg Nand 50 p.,g of EE 2. The intravenous doses were prepared by the G. D. Searle Laboratories when stability and sterility were also tested. The norethindrone for intravenous use was prepared in 5 ml ethyl alcohol: water (50: 50, v: v) and EE2 was prepared in a volume of 5 ml containing 1.5 ml of ethyl alcohol and 3.5 ml water. The intravenous
Norethindrone kinetics in women
449
preparations were diluted to 20 ml in sterile saline and given by slow intravenous infusion from separate syringes over 10 min with the subject supine. No ill effects were experienced during or after drug administration. Blood samples (20 ml) were taken into heparinized tubes through an indwelling intravenous cannula placed in the opposite arm at 0.5, 1.0, 2.0,3.0,4.0,6.0,8.0, 11.0, 14.0, and 24.0 hr after dosing. Additional blood samples were taken after the intravenous dose at 0.25, 0.75, and 1.5 hr after the infusion. Blood samples were centrifuged at 2,000 rpm for 10 min and the supernatant plasma was removed and stored at -25 0 C until analyzed. Plasma concentrations of norethindrone were measured by radioimmunoassav. 2
Calculations. Two-compartment open model analysis. The decline in plasma concentration of norethindrone with respect to time appeared biexponential and the data were therefore analyzed according to a two-compartment open model. 10 The plasma tV2 of norethindrone was calculated from the terminal part of the plasma disposition curve (f3 phase) with the use of a minimum of 4 points in all instances. The value of the rate constant for the initial (n:) disposition phase was calculated by means of residuals. The area under the plasma concentration time curve (AUC) from 0 to 24 hr was calculated by the trapezoidal rule with the use of a programmable pocket calculator (Texas S.R.52). The Aue from 24 hr to infinity was in each case less than 5% of the AUC from 0 to 24 hr. Bioavailability. The bioavailability (F) was calculated for each subject as the ratio between the areas under the oral and intravenous plasma concentration time curves corrected for the dose administered. The oral dose was I mg N acetate and 50 p.,g EE2 (1 mg N acetate === 0.8766 mg N). The results were tested for significance by means of Student's t test. Plasma clearance. Plasma clearance (Cl) was calculated from the equation: Cl =
FD AUC x BW
(I)
where F is the fraction of the dose (D) absorbed
Back et al.
450
Clin. Pharmacol. Ther. October 1978
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Fig. 1. Plasma concentrations of norethindrone after the administration of a single dose of norethindrone (I mg) to 6 subjects by both oral 1 mg N acetate and 50 t.tg EE2 and intravenous routes (mean ± SE).
Fig. 2. Plasma concentrations of norethindrone in Subject C. M. after the administration of 4 different preparations of norethindrone.
into the systemic circulation and BW is body weight.! Apparent volume of distribution.! The apparent volume of distribution (Vd area) was calculated as:
and 12.8 hr (mean, 7.6 hr). There were no significant differences between the values for the {3 phase t1;2 between the 4 preparations, the values being I mg N acetate and 50 /J-g EE 2 , 7.4 ± 0.69 hr (mean ± SE); intravenous dose, 8.0 ± 1.35 hr; 1.05 mg N, 7.7 ± 1.14 hr; and 3 mg N acetate and 50 /J-g EE 2, 7.5 ± 0.94 hr. Bioavailability. The values for the AVC measurements are shown in Table II. Comparison of the values for the intravenous dose (F = I) and the I mg N acetate and 50 /J-g EE2 preparation shows that norethindrone is not completely bioavailable. The mean value for F is 0.64 with a range of 0.47 to 0.73. There was no significant difference between the AVC value for 1.05 mg Nand 1 mg N acetate and 50 /J-g EE 2 • However, the AVC after 3 mg N acetate and 50 /J-g EE 2, when corrected for dosage, is less than that for 1 mg N acetate and 50 /J-g EE2 (0.52 ± 0.06 compared with 0.64 ± 0.04 P < 0.05). Expressed as a ratio, the norethindrone AVC 3 mg N acetate and 50 /J-g EE 2: I mg N acetate and 50 /J-g EE2 is 2.4: 1, although the dose ratio is 3: 1. Plasma clearance and apparent volumes of
VD area = CI/{3
(2)
where {3 is the rate constant of the terminal part of the concentration/time curve. Results
Intravenous dosing. Concentrations of norethindrone were measured in the first sample taken IS min after the end of the intravenous infusion and ranged between 12.0 and 29.0 ng/ml. Plasma concentrations decreased rapidly and after 4 to 6 hr a terminal single exponential phase followed (Fig. I). Oral dosing. N was absorbed rapidly after oral dosing, with peak plasma concentrations occurring in all cases by 2 hr and in most cases by I hr (Fig. 2). The values for a and {3 are given in Table I. The t1;2 of the initial (a) phase varied between 0.41 and 2.6 hr (mean, 1.17 hr) and the second ({3) phase t1;2 varied between 4.8
Norethindrone kinetics in women
Volume 24 Number 4
451
Table I. Rate constants of the fast disposition phase ( a) and the slow disposition phase (f3) after the administration of 4 preparations of norethindrone to 6 subjects (hr- I ) 1 mg N acetate and 50 fJ-g EE2 Patient
J.c.
P. C. R. C. M.O. C. M. M.R. Mean ±SE
a
I
a
f3
0.603 0.770 0.420 0.641 0.924 0.660 0.670 ±0.068
Intravenous dose
0.066 0.106 0.108 0.108 0.112 0.095 0.099 ±0.007
0.597 1.690 0.630 0.866 0.693 0.541 0.836 ±0.176
I
1.05 mg N acetate
f3
a
0.054 0.124 0.123 0.133 0.090 0.062 0.098 ±0.014
0.456 0.578 0.936 0.568 1.155 0.330 0.671 ±0.127
I
3 mg N acetate and 50 fJ-g EE2
f3
a
0.065 0.064 0.144 0.089 0.116 0.107 0.097 ±0.013
0.266 0.815 0.654 0.722 0.340 0.693 0.582 ±0.091
1
f3 0.064 0.076 0.126 0.090 0.112 0.117 0.097 ±0.01O
Table II. Areas under the plasma concentration/time curve (AUe) after 4 single doses of norethindrone to 6 normal subjects (hr x ng/ml) 1 mg N acetate and 50 pg EE2 Patient
AUC
I
J. C. 25.4 33.2 P. C. R. C. 32.6 M.O. 29.7 C.M. 37.4 M.R. 27.0 Mean 30.9 ±SE ±0.73 Significance compared with 1 mg N acetate and 50 fJ-g EE2 corrected to I mg dose
F 0.73 0.71 0.68 0.47 0.62 0.63 0.64 ±0.04
Intravenous dose AUC
I
35.0 47.0 47.6 62.6 60.4 42.8 49.2 ±1.76
distribution. The plasma clearances of norethindrone with I mg N acetate and 50 J,Lg EE 2,
1.05 mg N, and the intravenous preparation are shown in Table III. Because of the discrepancy of dose between the oral and intravenous routes, clearances of norethindrone with 3 mg N acetate and 50 J,Lg EE2 were not calculated. The mean plasma clearance of N after I mg N acetate and 50 J,Lg EE2 was 400.0 ± 31.7 ml/kg/hr, and there was no significant difference in the plasma clearance of norethindrone between the other preparations. The mean apparent volume of distribution of norethindrone with I mg N acetate and 50 J,Lg EE2 was 4.28 ± 0.56 Llkg which did not differ significantly after adminis-
F
1.05 mg N acetate AUC
I
29.0 34.9 39.6 22.2 28.3 25.8 29.9 ±1.06 p < 0.005
F 0.83 0.74 0.83 0.35 0.47 0.60 0.64 ±0.08 NS
3 mg N acetate and 50 fJ-g EE2
~UC_ 66.1 74.0 100.6 59.7 74.4 69.9 74.1 ±2.33
J
F -
0.63 0.52 0.70 0.32 0.41 0.54 0.52 ±0.06 P < 0.05
tration of the other preparations of norethindrone (Table I V). Discussion
These studies show that after a single dose, the disposition of norethindrone in plasma follows a biexponential pattern with an initial rapid phase lasting for up to 6 hr after dosing. This is followed by a slower, f3 phase with a tV2 of between 4.8 and 12.8 hr. These figures for the terminal phase tl/2 are in the range reported by other workers. 4, 6, 7, 9, 11 Ethinylestradiol did not alter the plasma tV2, plasma clearance, or apparent volume of distribution of norethindrone when the data following administration of
452
Back et al.
Clin. Pharmacal. Ther. October 1978
m.
Table Plasma clearances of norethindrone after the administration of 3 different preparations of norethindrone to 6 subjects mllkg/hr Patient
1. C. P. C. R. C. M.O. C.M. M.R. Mean ±SE Significance relative to I mg N acetate and 50 JLgEE 2
I mg N acetate and 50 JLg EE2
Intravenous dose
I.05 mg N acetate
427 464 443 319 267 480 400.0 ±31.7
374 407 388 279 260 422 355.0 ±27.9 NS
328 386 320 355 344 441 362.3 ±18.4 NS
Table IV. Apparent volumes of distribution of norethindrone after administration of three preparations of norethindrone to 6 subjects Llkg Patient
J. C. P. C. R. C. M.O. C. M. M.R. Mean ±SE Significance relative to I mg N acetate and 50 JLg EE2
I mg N acetate and 50 JLg EE2
Intravenous dose
I.05 mg N acetate
6.40 4.42 4.09 2.94 2.65 5.05 4.28 ±0.56
6.90 3.29 3.13 2.09 2.89 3.41 3.62 ±0.80 NS
5.01 6.02 2.21 3.99 2.98 4.13 4.06 ±0.56 NS
1.05 mg N (containing no EE 2 ) were compared with the data obtained with other preparations. We have also shown that the bioavailability of norethindrone is significantly less than 100% when given orally, with a mean bioavailability of 64% (range, 47% to 73%) compared with the intravenous formulation. This reduced bioavailability might be due to incomplete absorption but norethindrone is reported to be well absorbed after oral administration. 4 The reduced bioavailability of norethindrone may therefore be due to first-pass metabolism either in the liver or in the gut wall. Our studies do not enable us to differentiate between these two sites but it is known that the gut wall contributes
significantly to the first-pass effect of norethindrone in rats.3 It is of interest that another oral progestogen, levo norgestrel, has recently been shown not to have a first-pass effect in low doses. s The bioavailability of norethindrone after a 3-mg oral dose is significantly reduced, compared with a I mg oral dose of norethindrone with mean values of 52% and 64%, respectively. A similar finding has been demonstrated by Okerholm and associates. 8 Using much larger doses of norethindrone, they showed that the AVe after a single 20-mg oral dose of norethindrone was only twice the AVe after 5 mg norethindrone. In our study the AVe of nor-
Volume 24 Number 4
ethindrone after 3 mg N acetate and 50 p.g EE2 was only 2.4 times as great as that after I mg N acetate and 50 p.g EE 2 • These data are in agreement with the data in the previous paper showing plasma concentrations of norethindrone lower than predicted after multiple dosing with 3 mg N acetate and 50 p.g EE2 (8.3 ± 0.75 ng/ml) compared with I mg N acetate and 50 p.g EE2 (5.9 ± 0.47 ng/ml). We are unable to calculate the plasma clearances or apparent volumes of distribution of norethindrone after a 3-mg oral dose, since no 3-mg intravenous dose was given. A possible explanation is that with a larger single dose of norethindrone, the concentration of the drug in the hepatic portal vein may exceed the binding capacity of the sex hormone-binding globulin. This would lead to a resultant rise in the free concentration of norethindrone in the portal vein and an increased clearance of norethindrone from the plasma by the liver. We would like to thank the Mersey Regional Health Authority, the Wellcome Trust, G. O. Searle Pharmaceuticals, and the Peel Medical Trust for financial assistance. We thank Professor M. Row land for advice on pharmacokinetics.
Norethindrone kinetics in women
3.
4. 5.
6.
7.
8.
9.
References I. Alexandersson B: Pharmacokinetics of desmethylimipramine and nortryptiline in man after single and multiple oral doses-A cross over study. Eur J Clin Pharmacol 5:1-10,1972. 2. Back OJ, Breckenridge AM, Crawford FE, McIver M, Orme ML'E, Rowe PH. Smith E: Kinetics of norethindrone in women. I. Radio-
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II.
453
immunoassay and concentrations during multiple dosing. CUN PHARMACOL THER 1978. Back OJ, Breckenridge AM, Crawford FE, Orme ML'E, Rowe PH, Smith E: First-pass effect of norethindrone in rabbits and rats. J Pharmacol Exp Ther (In press.) Fotherby K, Warren RJ: Bioavailability of contraceptive steroids from capsules. Contraception 14:261-267, 1976. Humpel M, Wendt H, Pommerenke G, Weiss Chr, Speck U: Investigations of pharmacokinetics of levo norgestrel to specific considerations of a possible first-pass effect in women. Contraception 17 :207 -220, 1978. Mills TM, Lin TJ, Hemandez-Ayup S, Greenblatt RB, Ellegood 10, Mahesh YB: The metabolic clearance rate and urinary excretion of oral contraceptive drugs. I. Norethindrone. Am J Obstet Gynecol 120:764-772, 1974. Nygren KG, Lindberg P, Martinsson K, Bosu WTK, Johansson EOB: Radioimmunoassay of norethindrone: Peripheral plasma levels after oral administration to humans and rhesus monkeys. Contraception 9:265-278, 1974. Okemolm RA, Peterson FE, Keeley FJ, Smith TC, Glazko AJ: Bioavai!abi!ity of norethindrone in human subjects. Eur J Clin Pharmacol 13: 35-39, 1978. Pasqualini JR, Castellet R, Portois MC, Hill JL, Kincl FA: Plasma concentrations of ethinyloestradiol and norethisterone after oral administration to women. J Reprod Ferti! 49:189-193, 1977. Riegelman S, Loo JCK, Rowland M: Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J Pharm Sci 57: I 17-123, 1968. Warren RJ, Fotherby K: Radioimmunoassay of synthetic progestogens, norethisterone, and norgestrel. J Endocrinol 62:605-618, 1974.
