Summary
Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone.
The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The β-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 L/kg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/ml. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 ng/ml for norethisterone and 0.8 to 4.5 ng/ml for levonorgestrel.
All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin.
Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug.
The oral contraceptive steroids are involved in drug interactions of clinical significance. While the effect of contraceptive steroids on other drugs is small and unlikely to be of clinical significance, failure of contraception often occurs if enzyme-inducing agents such as rifampkin, phenobarbitone or carbamazepine are coadministered. Oral antibiotics do not seem to cause a significant loss of contraception in the large majority of women. Vitamin C will enhance the effect of contraceptive steroids by competing for sulphate conjugation in the gut wall, thus leading to increased bioavailability of ethinyloestradiol.
References
Abdel-Aziz, M.T. and Williams, K.I.H.: Metabolism of radioactive 17α-ethynylestradiol by women. Steroids 15: 695–710 (1970).
Abernethy, D.R. and Greenblatt, D.J.: Impairment of antipyrine metabolism by low dose oral contraceptive steroids. Clinical Pharmacology and Therapeutics 29: 106–110 (1981).
Adlercreutz, H.: Oestrogen metabolism in liver disease. Journal of Endocrinology 46: 129–163 (1970).
Adlercreutz, H.: Hepatic metabolism of estrogens in health and disease. New England Journal of Medicine 290: 1081–1083 (1974).
Adlercreutz, H.; Martin, F.; Wahlroos, O. and Soini, E.: Mass spectrometric and mass fragmentographic determination of natural and synthetic steroids in biological fluids. Journal of Steroid Biochemistry 6: 247–259 (1975).
Adlercreutz, H.; Martin, F.; Järvanpää, P. and Fotsis, T.: Steroid absorption and enterohepatic recycling. Contraception 20: 201–223 (1979).
Ahluwalia, B.S.; Curry, C.L.; Crocker, C.I. and Verma, P.S.: Evidence of higher ethynylestradiol blood levels in human hypertensive oral contraceptive users. Fertility and Sterility 28: 627–630 (1977a).
Ahluwalia, B.S.; Verma, P.S.; Greer, L.; Khanna, K.L. and Crocker, C.L.: Elevated caffeine and ethynylestradiol blood levels in hypertensive oral contraceptive users. Contraception 15: 465–471 (1977b).
Akpoviroro, J. and Fotherby, K.: Assay of ethinyloestradiol in human serum and its binding to plasma protein. Journal of Steroid Biochemistry 13: 773–779 (1980).
Akpoviroro, J.O.; Mangalam, M.; Jenkins, N. and Fotherby, K.: Binding of the contraceptive steroids medroxyprogesterone acetate and ethynylestradiol in blood of various species. Journal of Steroid Biochemistry 14: 493–498 (1981).
Anderson, D.C.: Sex hormone binding globulin. Clinical Endocrinology 3: 69–96 (1974).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; Maclver, M.; Orme, M.L.E.; Rowe, P.H. and Smith, E.: Pharmacokinetics of norethindrone in women. (2) Single dose pharmacokinetics. Clinical Pharmacology and Therapeutics 24: 448–453 (1978a).
Back, D.J.; Breckenridge, A.M.: Crawford, F.E.; Maclver, M.; Orme, M.L.E.; Rowe, P.H. and Smith, E.: The pharmacokinetics of norethindrone in women. (J) Radioimmunoassay and concentrations during multiple dosing. Clinical Pharmacology and Therapeutics 24: 439–447 (1978b).
Back, D.J.; Breckenridge, A.M.; Challiner, M.; Crawford, F.E.; Orme, M.L.E.; Rowe, P.H. and Smith, E.: The effect of antibiotics on the enterohepatic circulation of ethinyloestradiol and norethisterone in the rat. Journal of Steroid Biochemistry 9: 527–531 (1978c).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; Maclver, M.; Orme, M.L.E.; Rowe, P.H. and Watts, M.J.: An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay. Contraception 20: 263–273 (1979a).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; MacIver, M.; Orme, M.L.E.; Park, B.K.; Rowe, P.H. and Smith, E.: The effect of rifampicin on norethisterone pharmacokinetics. European Journal of Clinical Pharmacology 15: 193–197 (1979b).
Back, D.J.; Bates, M.; Burke, M.W.; Breckenridge, A.M.; Crawford, F.E.; MacIver, M.; Orme, M.L.E.; Rowe, P.H.; Smith, E. and Webster, S.: Plasma Xa inhibitory activities and plasma concentrations of norgestrel and ethinyloestradiol in women on oral contraceptive steroids. British Journal of Clinical Pharmacology 8: 505–506 (1979c).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; Orme, M.L.E.; Rowe, P.H. and Smith, E.: First pass effect of norethindrone in rabbits and rats. Journal of Pharmacology and Experimental Therapeutics 207: 555–565 (1979d).
Back, D.J.; Bates, M.; Breckenridge, A.M.; Crawford, F.E., Ellis, A.; Hall, J.M.; Maclver, M.; Orme, M.L.E. and Rowe, P.H.: Drug metabolism by gastrointestinal mucosa-clinical aspects; in Prescott and Nimmo (Eds) Drug Absorption pp.80–87 (ADIS Press, Sydney 1980a).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; Hall, J.M.; MacIver, M.; Orme, M.L.E; Rowe, P.H.; Smith, E. and Watts, M.J.: The effect of rifampicin on the pharmacokinetics of ethinyloestradiol in women. Contraception 21: 135–143 (1980b).
Back, D.J.; Bates, M.; Bowden, A.; Breckenridge, A.M.; Hall, M.J.; Jones, H.; Maclver, M.; Orme, M.L.E.; Perucca, A.; Richens, A.; Rowe, P.H. and Smith, E.: The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy. Contraception 22: 495–503 (1980c).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; Orme, M.L.E. and Rowe, P.H.: Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat. British Journal of Pharmacology 69: 441–452 (1980d).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; Cross, K.; Orme, M.L.E.; Percival, A. and Rowe, P.H.: Reduction of the enterohepatic circulation of norethisterone by antibiotics in the rat: Correlation with changes in the gut flora. Journal of Steroid Biochemistry 13: 95–100 (1980e).
Back, D.J.; Bolt, H.M.; Breckenridge, A.M.; Crawford, F.E.; Orme, M.L.E.; Rowe, P.H. and Schlindler, A.E.: The pharmacokinetics of a large (3 mg) oral dose of ethinyloestradiol in women. Contraception 21: 145–153 (1980f).
Back, D.J.; Bates, M.; Breckenridge, A.M.; Hall, J.M.; MacIver, M.; Orme, M.L.E.; Park, B.K. and Rowe, P.H.: The pharmacokinetics of levonorgestrel and ethinyloestradiol in women — studies with Ovran and Ovranette. Contraception 23: 229–239 (1981a).
Back, D.J.; Bates, M.; Breckenridge, A.M.; Ellis, A.; Maclver, M.; Orme, M.L.E. and Rowe, P.H.: The in vitro metabolism of ethinyloestradiol, mestranol and levonorgestrel by human jejunal mucosa. British Journal of Clinical Pharmacology 11: 275–278 (1981b).
Back, D.J.; Breckenridge, A.M.; MacIver, M.; Orme, M.L.E; Purba, H. and Rowe, P.H.: The interaction of ethinyloestradiol with ascorbic acid in man. British Medical Journal 282: 1516 (1981c).
Back, D.J.; Breckenridge, A.M.; Chapman, C.R.; Crawford, F.E.; Olsen, K.A.; Orme, M.L.E. and Rowe, P.H.: Studies on the enzymatic cleavage of norethisterone oenanthate. Contraception 23: 125–132 (1981d).
Back, D.J.; Breckenridge, A.M.; Crawford, F.E.; MacIver, M.; Orme, M.L.E. and Rowe, P.H.: Inter-individual variation and drug interactions with hormonal steroid contraceptives. Drugs 21: 46–61 (1981).
Back, D.J.; Breckenridge, A.M.; MacIver, M.; Orme, M.L.E; Purba, H.S.; Rowe, P.H. and Taylor, I.: The gut wall metabolism of ethinyloestradiol and its contribution to the pre-systemic metabolism of ethinyloestradiol in humans. British Journal of Clinical Pharmacology 13: 325–330 (1982a).
Back, D.J.; Breckenridge, A.M. and Orme, M.L.E.: Drug interactions involving oral contraceptive steroid therapy; in Cluff and Petrie (Eds) Clinically Important Adverse Drug Interactions, Volume 2 (Elsevier/North Holland, Amsterdam; in press, 1982b).
Back, D.J.; Barkfeldt, J.O.; Breckenridge, A.M.; Odlind, V.; Orme, M.L.E.; Park, B.K.; Purba, H.; Thia, J. and Victor, A.: The enzyme inducing effect of rifampicin in the rhesus monkey and its lack of interaction with oral contraceptive steroids. Contraception 25: 307–316 (1982c).
Back, D.J.; Breckenridge, A.M.; Cross, K.J.; Orme, M.L.E. and Thomas, E.: An antibiotic interaction with ethinyloestradiol in the rat and rabbit. Journal of Steroid Biochemistry 16: 407–413 (1982d).
Back, D.J.; Breckenridge, A.M.; MacIver, M.; Orme, M.L.E; Rowe, P.H., Staiger, Ch.; Thomas, E. and Tjia, J.: The effects of ampicillin on oral contraceptive steroids in women. British Journal of Clinical Pharmacology 14: 43–48 (1982e).
Backström, T. and Sodergard, R.: The influence of antiepileptic drugs on steroid plasma levels and binding during the menstrual cycle. Acta Endocrinologica Suppl. 212: 42 (1977).
Bacon, J.F. and Shenfield, G.M.: Pregnancy attributable to interaction between tetracycline and oral contraceptives. British Medical Journal 1: 293 (1980).
Ball, P.; Gelbke, H.P.; Haupt, O. and Knuppen, R.: Metabolism of 17α-ethynyl [4-14C] estradiol and [4-14C] mestranol in rat liver slices and interaction between 17α-ethynyl-2-hydroxyoestradiol and adrenalin. Hoppe-Seyler’s Zeitschrift fuer Physiologische Chemie 354: 1567–1575 (1973).
Beaumont, V.; Lemort, N.; Lorenzelli, L. and Beaumont, J.L.: Vascular thrombosis and oral contraceptives — a risk correlated study. Journal of Medicine 12: 51–61 (1981).
Bedolla-Tovar, N.; Rahman, S.A.; Cekan, S.Z. and Diczfalusy, E.: Assessment of the specificity of norethisterone radio-immunoassays. Journal of Steroid Biochemistry 9: 561–567 (1978).
Belaisch, J.; Driguez, P. and Janaud, A.: Influence de certains medicaments sur Taction des pilules contraceptives. Nouvelle Presse Medicale 5: 1645–1646 (1976).
Bessot, J-C.; Petitjean, R.; Vandevenne, A.; Rempp, M. and Burghard, G.: Interference de la rifampicine sur les contraceptifs oraux. Journal de Medecine de Strasbourg 8: 131–133 (1977).
Bhaskar, A.; Schulze, P.E.; Acksteiner, B. and Laumas, K.R.: Quantitative analysis of norethindrone in milk using deuterated carrier and gas chromatography-mass spectrometry. Journal of Steroid Biochemistry 11: 1323–1328 (1979).
Bird, C.E. and Clark, A.F.: Metabolic clearance rates and metabolism of mestranol and ethynylestradiol in normal young women. Journal of Clinical Endocrinology and Metabolism 36: 296–302 (1973).
Bolt, H.M.: Metabolism of estrogens — natural and synthetic. Pharmacology and Therapeutics 4: 155–181 (1979).
Bolt, H.M. and Bolt, W.H.: Pharmacokinetics of mestranol in man in relation to its oestrogenic activity. European Journal of Clinical Pharmacology 7: 295–305 (1974).
Bolt, H.M. and Remmer, H.: Retention, metabolism and elimination of 17α-ethynyl-estradiol-3-methyl ether (mestranol). Xenobiotica 2: 77–88 (1972).
Bolt, H.M.; Kappus, H. and Kasbohrer, R.: Metabolism of 17α-ethynylestradiol by human liver microsomes in vitro: Aromatic hydroxylation and irreversible protein binding of metabolites. Journal of Clinical Endocrinology and Metabolism 39: 1072–1080 (1974a).
Bolt, W.H.; Kappus, H. and Bolt, H.M.: Ring A oxidation of 17α-ethynylestradiol in man. Hormone and Metabolic Research 6: 432 (1974b).
Bolt, H.M.; Kappus, H. and Bolt, M.: The effect of rifampicin treatment on the metabolism of oestradiol and 17α-ethinyloestradiol by human liver microsomes. European Journal of Clinical Pharmacology 8: 301–307 (1975).
Bolt, H.M.; Bolt, M. and Kappus, H.: Interaction of rifampicin treatment with pharmacokinetics and metabolism of ethinyloestradiol in man. Acta Endocrinologica 85: 189–197 (1977).
Bowles, J.M. and Mills, R.J.: Sex hormone binding globulin: Effect of synthetic steroids on the assay and the effect of oral contraceptives. Annals of Clinical Biochemistry 18: 226–231 (1981).
Braselton, W.E.; Lin, T.J.; Mills, T.M.; Ellegood, J.O. and Mahesh, V.B.: Identification and measurement by gas chromatography mass-spectrometry of norethindrone and metabolites in human urine and blood. Journal of Steroid Biochemistry 8: 9–18 (1977).
Braselton, W.E.; Lin, T.J.; Ellegood, J.O.; Mills, T.M. and Mahesh, Y.B.: Accumulation of norethindrone and individual metabolites in human plasma during short- and long-term administration of a contraceptive dosage. American Journal of Obstetrics and Gynecology 133: 154–160 (1979).
Breckenridge, A.M.: Clinical implications of enzyme induction; in Parke (Ed.) Enzyme Induction, pp.278–301 (Plenum Press, London 1975).
Breckenridge, A.M.; Grabowski, P.S.; Maggs, J.L. and Park, B.K.: Inhibition of the irreversible binding of ethinyloestradiol to rat liver microsomes in vitro. British Journal of Pharmacology 74: 240P–241P (1981).
Brenner, P.F.; Mishell, D.R.; Stanczyk, F.Z. and Goebelsmann, U.: Serum levels of d-norgestrel, luteinizing hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel. American Journal of Obstetrics and Gynecology 129: 133–140 (1977).
Brenner, P.F.; Goebelsmann, U.; Stanczyk, F.Z. and Mishell, D.R.: Serum levels of ethinyloestradiol following its ingestion alone or in contraceptive formulations. Contraception 22: 85–93 (1980).
Breuer, H.: Metabolism of progestogens. Lancet 2: 615–616 (1970).
Brewster, D.; Jones, R.S. and Symons, A.M.: Effects of neomycin on the biliary excretion and enterohepatic circulation of mestranol and 17β-oestradiol. Biochemical Pharmacology 26: 943–946 (1977).
Briggs, M.H.: Hormonal contraceptives and plasma sex hormone binding globulin. Contraception 12: 149–153 (1975).
Briggs, M.H.: Comparative pharmacodynamics and pharmaco kinetics of contraceptive steroids in animals and man. A selective review; in Turner (Ed.) Clinical Pharmacology and Therapeutics; Proceedings of the First World Conference on Clinical Pharmacology and Therapeutics, London, UK, pp.493–518 (Macmillan Press, London 1980).
Briggs, M.H.: Megadose vitamin C and metabolic effects of the pill. British Medical Journal 283: 1547 (1981).
Brown, J.B. and Blair, H.A.F.: Urinary oestrogen metabolites of 19-norethisterone and its esters. Proceedings of the Royal Society of Medicine 53: 433 (1960).
Cameron, E.H.D.; Morris, S.E.; Scarisbrick, J.J. and Hillier, S.G.: Some observations on the use of 125I-labelled ligands in steroid radioimmunoassay. Biochemical Society Transactions 1: 1115–1117 (1973).
Cargill, D.I.; Steinetz, B.G.; Gosnell, E.; Beach, V.L.; Meli, A.; Fujimoto, G.I. and Reynolds, B.M.: Fate of ingested radio labelled ethynylestradiol and its 3-cyclopentyl ether in patients with bile fistulas. Journal of Clinical Endocrinology and Metabolism 29: 1051–1061 (1969).
Carter, D.E.; Goldman, J.M.; Bressler, R.; Huxtable, R.J.; Christian, C.D. and Heine, M.W.: Effect of oral contraceptives on drag metabolism. Clinical Pharmacology and Therapeutics 15: 22–31 (1974).
Chambers, D.M.; Jefferson, G.C.; Chambers, M. and Loudon, N.C.: Antipyrine elimination in saliva after low dose combined or progestogen only oral contraceptive steroids. British Journal of Clinical Pharmacology 13: 229–232 (1982).
Chowdhury, V.; Joshi, U.M.; Gopalkrishna, K.; Betrabet, S.; Mehta, S. and Saxena, B.M.: ‘Escape’ ovulation in women due to the missing of low dose combination oral contraceptive pills. Contraception 22: 241–247 (1980).
Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).
Conney, A.H.; Pantuck, E.J.; Pantuck, C.B.; Buening, M.; Jerina, D.M.; Fortner, J.G.; Alvares, A.P.; Anderson, K.E. and Kappas, A.: Role of environment and diet in the regulation of human drug metabolism; in Estabrook and Linderlaub (Eds) The Induction of Drug Metabolism, pp.583–605 (Springer Verlag, Stuttgart 1979).
Cook, C.E.; Twine, M.E.; Tallent, C.R.; Wall, M.E. and Bressler, R.: Norethynodrel metabolites in human plasma and urine. Journal of Pharmacology and Experimental Therapeutics 183: 197–205 (1972).
Cook, C.E.; Karim, A.; Forth, J.; Wall, M.E.; Ranney, R.E. and Bressler, R.C.: Ethynodiol diacetate metabolites in human plasma. Journal of Pharmacology and Experimental Therapeutics 185: 696–702 (1973).
Corker, C.S. and Exley, D.: The determination of plasma estradiol-17β by competitive protein binding radioassay. Steroids 15: 469–483 (1970).
Cortés-Gallegos, V.; Carranco, A.; Sojo, I.; Navarrette, M.; Cervantes, C. and Parra, A.: Accumulation of ethinyloestradiol in blood and endometrium of women taking oral contraceptives — the sequential therapy. Fertility and Sterility 32: 524–527 (1979).
Coulam, C.B. and Annegers, J.F.: Do anticonvulsants reduce the efficacy of oral contraceptives. Epilepsia 20: 519–526 (1979).
Crawford, F.E.; Back, D.J.; Orme, M.L.E. and Breckenridge, A.M.: Oral contraceptive steroid plasma concentrations in smokers and non-smokers. British Medical Journal 282: 1829–1830 (1981).
Danhof, M. and Breimer, D.D.: Therapeutic drug monitoring in saliva. Clinical Pharmacokinetics 3: 39–57 (1978).
de la Pena, A.; Chenault, C.B. and Goldzieher, J.: Radioimmunoassay of unconjugated plasma ethynylestradiol in women given a single dose of ethynylestradiol or mestranol. Steroids 25: 773–780 (1975).
Dennerstein, L.; Fotherby, K.; Burrows, G.D.; Laby, B. and Wood, C.: Plasma levels of ethynylestradiol and norgestrel during hormone replacement therapy. Maturitas 2: 147–154 (1980).
Diczfalusy, E.: Mode of action of contraceptive drugs. American Journal of Obstetrics and Gynecology 100: 136–163 (1968).
Dossetor, J.: Drug interactions with oral contraceptives. British Medical Journal 4: 467–468 (1975).
Düsterberg, R.; Hümpel, M. and Wendt, H.: Plasma levels of active ingredients after single and repeated administration of a new oral contraceptive containing 2mg of cyproterone acetate and 50μg of ethinyloestradiol (Diane) to five young women. Acta Obstetrica et Gynecologica Scandinavica Suppl. 88: 27–31 (1979).
Dyas, J.; Turkes, A.; Read, G.F. and Riad-Fahmy, D.: A radioimmunoassay for ethinyloestradiol in plasma incorporating an immunosorbent, pre-assay purification procedure. Annals of Clinical Biochemistry 18: 37–41 (1981).
Elstein, M.; Morris, S.E.; Groom, G.V.; Jenner, D.A.; Scarisbrick, J.J. and Cameron, E.H.D.: Studies on low dose oral contraceptives: Cervical mucus and plasma hormone changes in relation to circulating d-norgestrel and 17α-ethynyl-estradiol concentrations. Fertility and Sterility 27: 892–899 (1976).
Epstein, J.; Sobrero, A.; Rodriguez, A. and Krocin-Karacek, J.: A new oral estrogen with unusual properties. Clinical Research 13: 241 (1965).
Field, B.; Lu, C. and Hepner, G.W.: Inhibition of hepatic drug metabolism by norethindrone. Clinical Pharmacology and Therapeutics 25: 196–198 (1979).
Fishman, J.; Naftolin, F.; Davies, I.J.; Ryan, K.J. and Petro, Z.: Catechol estrogen formation by the human fetal brain and pituitary. Journal of Clinical Endocrinology and Metabolism 42: 177–180 (1976).
Fotherby, K.: Metabolism of synthetic steroids by animals and man; in Briggs and Diczfalusy (Eds) Pharmacological Models in Contraceptive Development, pp. 119–148 (WHO Stockholm 1974a).
Fotherby, K.: Metabolism of synthetic steroids by animals and man. Acta Endocrinologica Suppl. 185: 119–142 (1974b).
Fotherby, K. and Warren, R.J.: Bioavailability of contraceptive steroids from capsules. Contraception 14: 261–267 (1976).
Fotherby, K.; Kamyab, S.; Littleton, P. and Kjopper, A.: Metabolism of 17α-ethynyl steroids. Biochemical Journal 99: 14P (1966).
Fotherby, K.; Kamyab, S.; Littleton, P. and Klopper, A.: Metabolism of synthetic progestational compounds in humans. Journal of Reproduction and Fertility Suppl. 5: 51–61 (1968).
Fotherby, K.; Shrimanker, K.; Abdel-Rahman, H.A.; Toppozada, H.K.; De Souza, J.C.; Coutinho, E.M.; Koetsawang, S.; Nu-kulkarn, P.; Sheth, U.K.; Mapa, J.K.; Gopalan, S.; Plunkett, E.R.; Brenner, P.F.; Gomez-Rogers, C.; Kwon, E.; Kim, S.W.; Chan, T.; Ratnam, S.S.; Landgren, B.M. and Shearman, R.P.: Rate of metabolism of norethisterone in women from different populations. Contraception 19: 39–45 (1979a).
Fotherby, K.; Warren, R.J.; Shrimanker, K.; Siekmann, L.; Siekmann, A. and Breuer, H.: Plasma levels of norethisterone measured by radioimmunoassay and gas chromatography-mass fragmentography. Journal of Steroid Biochemistry 10: 121–122 (1979b).
Fotherby, K.; Akpoviroro, J.O.; Siekmann, L. and Breuer, H.: Measurement of ethynyloestradiol by radioimmunoassay and by isotope dilution-mass spectrometry. Journal of Steroid Biochemistry 14: 499–500 (1981a).
Fotherby, K.; Akpoviroro, J.; Abdel-Rahman, H.A.; Toppozada, H.K.; de Souza, J.C.; Coutinho, E.M.; Koetsawang, S.; Nukulkarn, P.; Sheth, U.K.; Mapa, M.K.; Gopalan, S.; Plunkett, E.R.; Brenner, P.F.; Hickey, M.V.; Grech, E.S.; Lichtenberg, R.; Gual, C.; Molina, R.; Gomez-Rogers, C.; Kwon, E.; Kim, S.W.; Chan, T.; Ratnam, S.S.; Landgren, B.M.; Shearman, R.P.: Goldzieher, J.W. and Dozier, T.S.: Pharmacokinetics of ethynylestradiol in women from different populations. Contraception 23: 489–496 (1981b).
Fotherby, K.: Pharmacokinetics of ethinyloestradiol in humans. Methods and Findings in Experimental and Clinical Pharmacology 4: 133–141 (1982).
Freudenthal, R.I.; Cook, C.E.; Forth, J.; Rosenfeld, R. and Wall, M.E.: The metabolism of ethynodiol diacetate by rat and human liver. Journal of Pharmacology and Experimental Therapeutics 177: 468–473 (1971).
Friedman, C.I.; Huneke, A.L.; Kim, M.H. and Powell, J.: The effect of ampicillin on oral contraceptive effectiveness. Obstetrics and Gynecology 55: 33–37 (1980).
Gagnaire, J.C.; Tchertchian, J.; Revol, A. and Rochet, Y.: Grossesses sous contraceptifs oraux chex les patients recevant des barbituriques. Nouvelle Presse Medicate 4: 3008 (1975).
Gerhards, E.; Hecker, W.; Hitze, H.; Nieuweboer, B. and Bellman, O.: Zumstoffwechsel von norethisterone (17α-äthinyl-4-östren-17β-ol-3-on) und dl-sowie d-norgestrel (18-methyl-17α -äthinyl-4-östren-17β -ol-3-on) beim menschen. Acta Endocrinologica 68: 219–248 (1971).
Giannina, T.; Steinetz, B.G.; Rassaert, C.L.; McDougall, E.A. and Meli, A.: Biological profile of Quingestanol Acetate. Proceedings of the Society for Experimental Biology and Medicine 131: 781–789 (1969).
Goldzieher, J.W. and Kraemer, D.C.: The metabolism and effects of contraceptive steroids in primates. Acta Endocrinologica Suppl. 166: 389–421 (1972).
Goldzieher, J.W.; de la Pena, A.; Chenault, C.B. and Wouterz, T.B.: Comparative studies of ethynylestrogens used in oral contraceptives. II. Anti-ovulatory potency. American Journal of Obstetrics and Gynecology 122: 619–624 (1975).
Goldzieher, J.W.; Dozier, T.S.; de la Pena, A.; Ojo, O.A.; Lean, T.S.; Chinnatamby, S.; Basnayake, S. and Koetsawang, S.: Plasma levels and pharmacokinetics of ethynylestrogens in various populations. Contraception 21: 1–16 (1980a).
Goldzieher, J.W.; Dozier, T.S.; de la Pena, A.; Ojo, O.A.; Lean, T.S.; Chinnatamby, S.; Basnayake, S. and Koetsawang, S.: Plasma levels and pharmacokinetics of ethynylestrogens in various populations. II. Mestranol. Contraception 21: 17–27 (1980b).
Hanasono, G.K. and Fischer, L.J.: The excretion of tritium-la-belled chlormadinone acetate, mestranol, norethindrone, and norethynodrel in rats and the enterohepatic circulation or metabolites. Drug Metabolism and Disposition 2: 159–168 (1974).
Handy, R.W.; Dominquez, D.; Poirier, M.; Wall, M.E.; Cook, C.E.; Christian, C.D. and Bressler, R.: Metabolism of norethynodrel in thrombophlebitic-thromboembolic subjects. Experientia 31: 416–417 (1975).
Heikkila, M.; Haukkamaa, M. and Luukainen, T.: Levonorgestrel in milk and plasma of breast-feeding women with a levon-orgestrel-releasing IUD. Contraception 25: 41–49 (1982).
Helton, E.D. and Goldzieher, J.W.: Metabolism of ethynyl estrogens. Journal of Toxicology and Environmental Health 3: 231–241 (1977a).
Helton, E.D. and Goldzieher, J.W.: The pharmacokinetics of the ethynyl estrogens. Contraception 15: 255–284 (1977b).
Helton, E.D.; Williams, M.C. and Goldzieher, J.W.: Human urinary and liver conjugates of 17α-ethynyloestradiol. Steroids 27: 851–867 (1976).
Helton, E.D.; Williams, M.C. and Goldzieher, J.W.: Oxidative metabolism and de-ethynylation of 17α-ethynylestradiol by baboon liver microsomes. Steroids 30: 71–83 (1977a).
Helton, E.D.; Simmons, R.; Meltz, M.L. and Goldzieher, J.W.: Variability in conjugates of ethynylestradiol produced by in vitro incubation of human liver tissue. Contraception 16: 257–260 (1977b).
Helton, E.D.; Hadd, H.E.; Williams, M.C.; Rao, P.N. and Goldzieher, J.W.: Synthesis of 17β-D-glucopyranosiduronic acid of 17α-ethynylestradiol. Journal of Steroid Biochemistry 9: 237–238 (1978).
Hempel, Von E.; Böhm, W.; Carol, W. and Klinger, W.: Meditamentose enzyminduktion und hormonale kontrazeption. Zentrablatt für Gynakologie 95: 1451–1457 (1973).
Hendeles, S.M.; Galand, N. and Schwere, J.: Metabolism of orally administered d-norgestrel in women. Acta Endocrinologica 71: 557–568 (1972).
Heubel, F. and Netter, K.J.: Atypical inducing properties of rifampicin. Biochemical Pharmacology 28: 3373–3378 (1979).
Hillier, S.G. and Read, G.F.: Radioimmunoassay for plasma norethisterone and testosterone using anlisera raised against C-11 conjugated haptens and radio-iodinated ligands. Journal of Endocrinology 67: 5P–6P (1975).
Hirai, S.; Hussain, A.; Haddadin, M. and Smith, R.B.: First pass metabolism of ethinyl estradiol in dogs and rats. Journal of Pharmaceutical Sciences 70: 403–406 (1981).
Hirsch, A.: Pilules endormies. Nouvelle Presse Medicate 2: 2957 (1973).
Hirsch, A.; Tillement, J.P. and Chretian, J.J.: Effets contrariants de la rifampicine sur les contraceptifs oraux: A propos de trois grossesses non-desireés chez trois malades. Revue Francais des Maladies Respiratoires 3: 174–182 (1975).
Houston, J.B. and Levy, G.: Modification of drug biotransformation by vitamin C in man. Nature 255: 78–79 (1975).
Hümpel, M.; Wendt, H.; Dogs, G.; Weiss, Chr.W.; Rietz, S. and Speck, U.: Intraindividual comparison of pharmacokinetic parameters of d-norgestrel, lynestrenol, and cyproterone acetate in 6 women. Contraception 16: 199–215 (1977).
Hümpel, M.; Wendt, H.; Pommerenke, G.; Weiss, C. and Speck, W.: Investigations of pharmacokinetics of levonorgestrel to specific consideration of a possible first pass effect in women. Contraception 17: 207–220 (1978).
Hümpel, M.; Nieuweboer, B.; Wendt, H. and Speck, U.: Investigations of pharmacokinetics of ethinyloestradiol to specific consideration of a possible first-pass effect in women. Contraception 19: 421–432 (1979).
Ishihara, M.; Osawa, Y.; Kirdani, R.Y. and Sandberg, A.A.: Metabolic fate of ethynodiol diacetate in the baboon. Steroids 25: 829–847 (1975).
Janz, D. and Schmidt, D.: Antiepileptic drugs and failure of oral contraceptives. Lancet 1: 113 (1974).
Janz, D. and Schmidt, D.: Antiepileptika und die Sicherheit oraler kontrazeptiva. Bibliographica Psychiatrica 151: 82–84 (1975).
Järvenpää, P.; Kosunen, T.; Fotsis, T. and Adlercreutz, H.: In vitro metabolism of estrogens by isolated intestinal microorganisms and by human faecal microflora. Journal of Steroid Biochemistry 13: 345–349 (1980).
Jellinck, P.H.: The excretion of synthetic oestrogens. Biochemical Journal 58: 262–265 (1954).
Jenkins, N. and Fotherby, K.: Binding of the contraceptive steroids norgestrel and norethisterone in human plasma. Journal of Steroid Biochemistry 13: 521–527 (1980).
Jenkins, N. and Fotherby, K.: Binding of the gestagens in norethisterone and levonorgestrel in blood of various species. Journal of Steroid Biochemistry 14: 1055–1062 (1981).
Jenkins, N.; Akpoviroro, J.; Mathrubatan, M. and Fotherby, K.: Binding of contraceptive steroids to plasma proteins of various species. Journal of Endocrinology 87: 12P (1980).
Johnston, M.A.: General method for the assay of oral contraceptives by high performance liquid chromatography. Journal of Chromatography 216: 269–278 (1981).
De Jongh, D.C.; Hribar, J.D.; Littleton, P.; Fotherby, K.; Rees, R.W.A.; Schrader, S.; Foell, T.J. and Smith, H.: The identification of some human metabolites of norgestrel, a new progestational agent. Steroids 11: 649–666 (1968).
Joshi, J.V.; Joshi, U.M.; Sankhali, G.M.; Krishna, U.; Mandlekar, A.; Chowdhury, V.; Hazari, K.; Gupta, K.; Sheth, U.K. and Saxena, B.W.: A study of interaction of low dose combination oral contraceptive with ampicillin and metronidazole. Contraception 22: 643–652 (1980).
Kamyab, S.; Fotherby, K. and Klopper, A.I.: Metabolism of (4−14C) lynestrenol in man. Journal of Endocrinology 42: 337–343 (1968a).
Kamyab, S.; Fotherby, K. and Klopper, A.I.: Metabolism of (4−14C) norethisterone in women. Journal of Endocrinology 41: 263–272 (1968b).
Kamyab, S.; Fotherby, K. and Steele, S.J.: Metabolism of [14C]-ethynylestradiol in women. Nature 221: 360–361 (1969).
Kanluan, T.; Masironi, B. and Cekan, S.A.: On the validity of a levonorgestrel radioimmunoassay. Clinica Chimica Acta 109: 169–174 (1981).
Kappus, H.; Bolt, H.M. and Remmer, H.: Demethylation of mestranol to ethinyloestradiol in vitro and in vivo. Acta Endocrinologica 71: 374–384 (1972).
Kappus, H.; Bolt, H.M. and Remmer, H.: Irreversible protein binding of metabolites of ethynylestradiol in vivo and in vitro. Steroids 22: 203–225 (1973).
Kaufman, J.M.; Thiery, M. and Vermeulen, A.: Plasma levels of ethinyloestradiol (EE) during cyclic treatment with combined oral contraceptives. Contraception 24: 589–602 (1981).
Kaul, L.; Curry, C.L. and Ahluwalia, B.S.: Blood levels of ethynylestradiol, caffeine, aldosterone and desoxycorticosterone in hypertensive oral contraceptive users. Contraception 23: 643–652 (1981).
Keay, G.R.: Analytical evaluation of gestogens in oral contraceptives. Analyst 93: 28–33 (1968).
Kenyon, T.E.: Unplanned pregnancy in an epileptic. British Medical Journal 1: 686–687 (1972).
Khurana, R.C.: Estrogen-imipramine interaction. Journal of the American Medical Association 222: 702–703 (1972).
Kishimoto, Y.; Kraychy, S.; Ranney, R.E. and Gantt, C.L.: Metabolism of oral contraceptives. I. Metabolism of ethynodiol diacetate in women. Xenobiotica 2: 237–252 (1972a).
Kishimoto, Y.; Kraychy, S.; Ranney, R.E.; Zitzewitz, D.J. and Gantt, C.L.: Metabolism of oral contraceptives. II. Metabolism of norethynodrel in women. Xenobiotica 2: 253–258 (1972b).
Korenman, S.G.; Perrin, L.E. and McCallum, T.P.: A radioligand binding assay system for estradiol measurement in human plasma. Journal of Clinical Endocrinology and Metabolism 29: 879–883 (1969a).
Korenman, S.G.; Perrin, L.E. and McCallum, T.: Estradiol in human plasma: Demonstration of elevated levels in gynaecomastia and in cirrhosis. Journal of Clinical Investigation 48: 45a (1969b).
Kropp, R.: Rifampicin und Ovulationshemmer. Praxis der Pneumologie 28: 270–272 (1974).
Kulkarni, B.D. and Goldzieher, J.W.: A preliminary report on urinary excretion pattern and method of isolation of 14C-ethynylestradiol metabolites in women. Contraception 1: 47–55 (1970a).
Kulkarni, B.D. and Goldzieher, J.W.: Urinary excretion pattern and fractionation of radioactivity after injection of 4-14C-mestranol in women. Contraception 1: 131–136 (1970b).
Kundu, N.: Radioimmunoassay of contraceptive steroids. II. Synthesis of 6,7-3-H-mestranol and ethinyloestradiol of high specific activity. Steroids 23: 155–163 (1974).
Kundu, N.; Keenan, S. and Slaunwhite, W.R.: Production of antisera against contraceptive steroids. Steroids 30: 85–98 (1977).
Lafaix, Ch.; Cadoz, M.; Richard, A. and Patouillard, P.: L’effect ‘antipilule’ de la rifampicine. Medicine et Hygiene 1181: 181–182 (1976).
Lähteenmäki, P. and Nilsson, C.G.: Plasma concentrations of ethinyloestradiol and d-norgestrel during immediate post abortal oral contraceptive cycles. Contraception 17: 9–17 (1978).
Langecker, H.: Die metabolite in menschlichen Harn nach Verabreichung von 17α-aethinyl-19-nortestosterone (Noreaethisteron). Acta Endocrinologica 37: 14–18 (1961).
Laragh, J.H.; Sealey, J.E.; Ledingham, J.G.G. and Newton, M.A.: Oral contraceptives. Renin, aldosterone and high blood pressure. Journal of the American Medical Association 201: 918–922 (1967).
Larranaga, A. and Berman, E.: Clinical study of a once a month oral contraceptive: Quinestrenol — Quingestanol. Contraception 1: 137–148 (1970).
Laumas, K.R.; Malkani, P.K.; Bhatnagar, S. and Laumas, V.: Radioactivity in the breast milk of lactating women after oral administration of 3H-norethynodrel. American Journal of Obstetrics and Gynecology 98: 411–413 (1967).
Laumas, K.R.; Murugesan, K. and Hingorani, V.: Disappearance in plasma and tissue uptake of radioactivity after intravenous injection of [3H] norethynodrel in women. Acta Endocrinologica 66: 385–400 (1971).
Layne, D.S.; Golab, T.; Arai, K. and Pincus, G.: The metabolic fate of orally administered 3H-norethynodrel and 3H-norethindrone in humans. Biochemical Pharmacology 12: 905–911 (1963).
Leigh, D.A.; Reeves, D.S.; Simmons, K.; Thomas, A.L. and Wilkinson, P.J.: Talampicillin: A new derivative of ampicillin. British Medical Journal 2: 1378–1380 (1976).
Lewis, C.J.; Vose, C.W.; Spalton, P.N.; Ford, G.C.; Haskins, N.J. and Palmer, R.F.: Metabolism of ethynodiol diacetate in the rhesus monkey before and after administration of rifampicin. Xenobiotica 10: 705–713 (1980).
Lipsett, M.B.: Factors influencing the rate of metabolism of steroid hormones in man. Annals of the New York Academy of Sciences 179: 442–449 (1971).
Littleton, P.; Fotherby, K. and Dennis, K.J.: Metabolism of (14C)-norgestrel in man. Journal of Endocrinology 42: 591–598 (1968).
Longcope, C. and Williams, K.I.H.: The metabolism of synthetic oestrogens in non-users and users of oral contraceptives. Steroids 25: 121–133 (1975).
Longcope, C.; Yesair, D.W.; Williams, K.I.H.; Callahan, M.M.; Bourget, C.; Brown, S.K.; Carraher, M.S.; Flood, C. and Rachwall, P.C.: Comparison of the metabolism in dogs of estradiol- 17β following its intravenous and oral administration. Journal of Steroid Biochemistry 13: 1047–1055 (1980).
Loo, J.C.K. and Brien, R.: Analysis of norethindrone in plasma by high-performance liquid chromatography. Journal of Liquid Chromatography 4: 871–877 (1981).
Lunell, N-O.; Carlström, K. and Zador, G.: Ovulation inhibition with a combined oral contraceptive containing 20μg ethinyloestradiol and 250μg levonorgestrel. Acta Obstetrica et Gynecologica Scandinavica Suppl 88: 17–21 (1979).
Martin, A.P.; Halterman, D.R.; Vorbeck, M.L.; Kuo, M.C. and Lucas, F.V.: Metabolism of norethynodrel, a 19-NOR progestin: Subcellular localization of enzyme activity. Steroids 16: 487–493 (1970).
Mazaheri, A.; Fotherby, K. and Chapman, J.R.: Metabolism of lynestrenol to norethisterone by liver homogenate. Journal of Endocrinology 47: 251–252 (1970).
Meade, T.W.; Brozovic, M.; Chakrabarti, R.; Howarth, D.J.; North, W.R.S. and Stirling, Y.: An epidemiological study of the haemostatic and other effects of oral contraceptives. British Journal of Haematology 34: 353–364 (1976).
Mills, T.M.; Lin. T.J.; Hernandez-Ayup, S.; Greenblatt, R.B.; Ellegood, J.O. and Mahesh, Y.B.: The metabolic clearance rate and urinary excretion of oral contraceptive drugs. I. Norethindrone. American Journal of Obstetrics and Gynecology 120: 722–764 (1974a).
Mills, T.M.; Lin, T.J.; Hernandez-Ayup, S.; Greenblatt, R.B.; Ellegood, J.O. and Mahesh, V.B.: The metabolic clearance rate and urinary excretion of oral contraceptive drugs. II. Mestranol. American Journal of Obstetrics and Gynecology 120: 773–778 (1974b).
Mills, T.M.; Lin, T.J.; Braselton, W.E.; Ellegood, J.O. and Mahesh, V.B.: Metabolism of oral contraceptive drugs. The formation and disappearance of metabolites of norethindrone and mestranol after intravenous and oral administration. American Journal of Obstetrics and Gynecology 126: 987–992 (1976).
Morris, S.E. and Cameron, E.H.D.: Radioimmunoassay system for norethisterone using 3H- and 125-labelled radioligands. Journal of Steroid Biochemistry 6: 1145–1150 (1975).
Morris, S.E.; Scarisbrick, J.J.; Cameron, E.H.D.; Groom, G.V.; Buckingham, M.S.; Everitt, J. and Elstein, M.: Comparison of plasma hormone changes using a “conventional” and a “paper pill” formulation of a low-dose oral contraceptive. Fertility and Sterility 29: 296–303 (1978).
Morvay, J.; Fotherby, K. and Altorjay, I.: Rapid radioimmunoassay (RIA) of ethinyloestradiol in body fluids. Clinica Chimica Acta 108: 147–150 (1980).
Mucklow, J.C.; Bending, M.R.; Kahn, G.C. and Dollery, C.T.: Drug concentrations in saliva. Clinical Pharmacology and Therapeutics 24: 563–570 (1978).
Murata, S.: Metabolism of 17α-ethynyl-19 nortestosterone and 17α-ethynylestradiol in vivo. Nippon Naibunpi Gakkai Zasshi. 43: 1083–1096 (1968).
Murugesan, K.; Hingorani, V. and Laumas, K.R.: In vitro metabolism of [6,7-3H] norethynodrel in the human endometrium and the myometrium. Acta Endocrinologica 74: 576–591 (1973).
Nair, K.M.; Sivakumar, B.; Prema, K. and Rao, B.S.N.: Pharmacokinetics of levonorgestrel in Indian women belonging to a low socio-economic group. Contraception 20: 303–317 (1979).
Newton, M.A.; Sealey, J.E.; Ledingham, J.G.G. and Laragh, J.H.: High blood pressure and oral contraceptives. Changes in plasma renin and renin substrate and in aldosterone excretion. American Journal of Obstetrics and Gynecology 101: 1037–1045 (1968).
Nilsson, S. and Nygren, K-G.: Ethinyloestradiol in peripheral plasma after oral administration of 30μg and 50μg to women. Contraception 18: 469–475 (1978).
Nilsson, S.; Nygren, K-G. and Johansson, E.D.B.: d-Norgestrel concentrations in maternal plasma, milk and child plasma during administration of oral contraceptives to nursing women. American Journal of Obstetrics and Gynecology 129: 178–184 (1977a).
Nilsson, S.; Victor, A. and Nygren, K-G.: Plasma levels of d-norgestrel and sex hormone binding globulin during oral d-norgestrel medication immediately after delivery and legal abortion. Contraception 15: 87–92 (1977b).
Nilsson, S.; Nygren, K-G. and Johansson, E.D.B.: Ethinyl estradiol in human milk and plasma after oral administration. Contraception 17: 131–139 (1978).
Nocke-Fink, L.; Breuer, H. and Reimers, D.: Wirkung von rif-ampicin auf den menstruation zyklus die ostrogen-ausschie-dung bei einnahme oraler kontrazeptiva. Deutsche Medizinische Wochenschrift 98: 1521–1523 (1973).
Nygren, K-G.; Lindberg, P.; Martinsson, K.; Bosu, W.T.K. and Johansson, E.D.B.: Radioimmunoassay of norethindrone; peripheral plasma levels after oral administration to humans and rhesus monkeys. Contraception 9: 265–278 (1974).
Odlind, V. and Johansson, E.D.B.: Free norethisterone as reflected by saliva concentrations of norethisterone during oral contraceptive use. Acta Endocrinologica 98: 470–476 (1981).
Odlind, V.; Weiner, E.; Victor, A. and Johansson, E.D.B.: Plasma levels of norethindrone after single oral dose administration of norethindrone and lynestrenol. Clinical Endocrinology 10: 29–38 (1979a).
Odlind, V.; Weiner, E. and Johansson, E.D.B.: Plasma levels of norethindrone and effects upon ovarian function during treatment with silastic implants containing norethindrone. Contraception 19: 197–206 (1979b).
Odlind, V.; Weiner, E.; Victor, A. and Johansson, E.D.B.: Effects on sex hormone binding globulin of different oral contraceptives containing norethisterone and lynestrenol. British Journal of Obstetrics and Gynaecology 87: 416–421 (1980).
Okada, H.; Amatsu, M.; Ishihara, S. and Tokuda, G.: Conversion of some progestins to oestrogens. Acta Endocrinologica 46: 31–36 (1964).
Okerholm, R.A.; Peterson, F.E.; Keeley, F.J.; Smith, T.C. and Glazko, A.J.: Bioavailability of norethindrone in human subjects. European Journal of Clinical Pharmacology 13: 35–39 (1978).
O’Malley, K.; Stevenson, I.; Crooks, J.: Impairment of human drug metabolism by oral contraceptive steroids. Clinical Pharmacology and Therapeutics 13: 552–557 (1972).
O’Reilly, R.A.: Interaction of sodium warfarin and rifampicin (studies in man). Annals Int. Med. 81: 337–340 (1974).
Orme, M.L.E.: Clinical pharmacology of oral contraceptive steroids. British Journal of Clinical Pharmacology 14: 31–42 (1982).
Padova, C. di.; Tritapepe, R.; Cammareri, G.; Humpel, M. and Stramentinoli, G.: S-Adenosyl-L-methionine antagonizes ethynylestradiol-induced bile cholesterol supersaturation in humans without modifying the estrogen plasma kinetics. Gastroenterology 82: 223–227 (1982).
Pala, A. and Benagiano, G.: A direct radioiodination technique for the radioimmunoassay of 17α-ethynyl, 17β-hydroxy-4-estren-3-one. Journal of Steroid Biochemistry 7: 491–496 (1976).
Palmer, K.H.; Ross, F.T.; Rhodes, L.D.; Baggett, B. and Wall, M.E.: Metabolism of antifertility steroids. 1. Norethynodrel. Journal of Pharmacology and Experimental Therapeutics 167: 207–216 (1969a).
Palmer, K.H.; Feierabend, J.F.; Baggett, B. and Wall, M.E.: Metabolic removal of a 17α-ethynyl group from the antifertility steroid norethindrone. Journal of Pharmacology and Experimental Therapeutics 167: 217–222 (1969b).
Palmer, K.H.; Smith, D.J.S.; Liepins, L.; Feierabend, J.F. and Wall, M.E.: Metabolism of antifertility steroids. VI. Norethisterone. Pharmacologist 12: 254 (1970).
Pasqualini, J.R.; Castellet, R.; Portois, M.C.; Hill, J.L.; Kincl, F.A. and Cortes Prieto, J.: Radioimmunoassay of norethindrone (17α-ethinyl-17β-hydroxy-4-estren-3-one) and ethynylestradiol (17α-ethinyl-1,3,5(10) estratrien 3, 17β-diol). Application to human plasma determination of norethindrone after oral administration of this steroid. Reproduction 2: 197–205 (1975).
Pasqualini, J.R.; Castellet, R.; Portois, M.C.; Hill, J.L. and Kincl, F.A.: Plasma concentrations of ethynyl estradiol and norethindrone after oral administration to women. Journal of Reproduction and Fertility 49: 189–193 (1977).
Petitti. D.B. and Wingerd, J.: Use of oral contraceptives, cigarette smoking and risk of subarachnoid haemorrhage. Lancet 2: 234–235 (1978).
Piguet, B.; Muglioni, J.F. and Chaline, G.: Contraception orale et rifampicine. Nouvelle Presse Medicale 4: 115–117 (1975).
Pincus, G.; Bialy, G.; Layne, D.S.; Paniagua, M. and Williams, K.I.H.: Radioactivity in the milk of subjects receiving radioactive 19-norsteroids. Nature 212: 924–925 (1966).
Pogmore, J.R. and Jequier, A.M.: Effects of varying amounts of ethinyloestradiol in the combined oral contraceptive on plasma sex hormone binding globulin capacity in normal women. British Journal of Obstetrics and Gynaecology 86: 563–567 (1979).
Prange, A.J.: Estrogen may well affect the response to antidepressants. Journal of the American Medical Association 219: 143–144 (1972).
Prasad, K.V.S.; Narasinga Rao, B.S.; Sivakumar, B. and Prema, K.: Pharmacokinetics of norethindrone in Indian women. Contraception 20: 77–90 (1979a).
Prasad, K.V.S.; Sivakumar, B. and Narasinga Rao, B.S.: The rabbit as an animal model to study pharmacokinetics of norethindrone in women. Contraception 20: 619–632 (1979b).
Raitano, L.A.; Slikker, W.; Hill, D.E.; Hadd, H.E.; Cairns, T. and Helton, E.D.: Ethynyl cleavage of 17α-ethynylestradiol in the rhesus monkey. Drug Metabolism and Disposition 9: 129–134 (1981).
Ranney, R.E.: The comparative metabolism of mestranol and ethinyl estradiol in women and in experimental animals. Terapia Antibiotica et Chemioterapi 20: 65–69 (1970).
Ranney, R.E.: Comparative metabolism of 17α-ethinyl steroids used in oral contraceptives. Journal of Toxicology and Environmental Health 3: 139–166 (1977).
Rao, P.N.; De la Pena, A. and Goldzieher, J.W.: Antisera for radioimmunoassay of 17α-ethynylestradiol and mestranol. Steroids 24: 803–808 (1974).
Reed, M.J. and Fotherby, K.: Intestinal absorption of synthetic steroids. Journal of Steroid Biochemistry 11: 1107–1112 (1979).
Reed, M.J. and Fotherby, lt.: Interaction of ethynylestradiol sulphate with plasma proteins. Journal of Steroid Biochemistry 13: 495–497 (1980).
Reed, M.J.; Fotherby, K. and Steele, S.J.: Metabolism of ethynylestradiol in man. Journal of Endocrinology 55: 351–361 (1972).
Reed, M.J.; Fotherby, K.; Peck, J.E. and Gordon, Y.: Localization of norethisterone in the reproductive tract of women. Journal of Endocrinology 59: 569–577 (1973).
Reimers, D. and Jezek, A.: Rifampicin und andere antituberkulostatika bei gleichzeitiger oraler kontrazeption. Praxis der Pneumologie 25: 255–262 (1971).
Rizk, M.; Vallon, J.J. and Badinand, A.: Dosage colimetrique des Steroides acetyleniques à l’aide des ions Ag+. Clinica Chimica Acta 65: 220–222 (1973).
Roberton, Y.R. and Johnson, E.S.: Interactions between oral contraceptives and other drugs — a review. Current Medical Research and Opinion 3: 647–661 (1976).
Sahlberg, B-L.; Axelson, M.; Collins, D.J. and Sjövall, J.: Analysis of isomeric ethynylestradiol glucuronides in urine. Journal of Chromatography 217: 453–461 (1981).
Sankolli, G.M.; Naik, V.R.; Prasad, K.V.S.; Nair, M. and Joshi, U.M.: Influence of antisera on the estimations of norethisterone and levonorgestrel. Journal of Steroid Biochemistry 11: 1159–1163 (1979).
Saxena, B.M.; Shrimanker, K. and Grudzinskas, J.G.: Levels of contraceptive steroids in breast milk and plasma of lactating women. Contraception 16: 605–613 (1977).
Schrogie, J.J.; Soloman, H.M. and Zieve, P.D.: Effect of oral contraceptives on vitamin K dependent clotting activity. Clinical Pharmacology and Therapeutics 8: 670–675 (1967).
Shrimanker, K.; Akpoviroro, J.; Fotherby, K. and Watson, J.: Bioavailability of lynestrenol. Arzneimittel-Forschung 30: 500–502 (1980).
Siekmann, L.; Siekmann, A. and Breuer, H.: Monitoring of the oral contraceptives 17α-ethinyloestradiol-17β in human plasma by isotope dilution mass spectrometry. Frezenius’ Zeitschrift fuer Analytische Chemie 290: 159–160 (1978).
Siekmann, L.; Siekmann, A. and Breuer, H.: Measurement by isotope dilution mass spectrometry of 17α-ethinyl-estradiol-17β and norethisterone in serum of women taking oral contraceptives. Biomedical Mass Spectrometry 7: 511–514 (1980).
Singh, H.; Uniyal, J.P.; Murugesan, K.; Takkar, D.; Hingorani, V. and Laumas, K.R.: Pharmacokinetics of norethindrone acetate in women. American Journal of Obstetrics and Gynecology 135: 409–414 (1979).
Sisenwine, S.F.; Kimmel, H.B.; Liu, A.L. and Ruelius, H.W.: Urinary metabolites of DL-norgestrel in women. Acta Endocrinologica 73: 91–104 (1973).
Sisenwine, S.F.; Kimmel, H.B.; Liu, A.L. and Ruelius, H.W.: The presence of dl, d- and l-norgestrel and their metabolites in the plasma of women. Contraception 12: 339–353 (1975a).
Sisenwine, S.F.; Kimmel, H.B.; Liu, A.L. and Ruelius, H.W.: Excretion and stereoselective biotransformations of dl-, d-, and l-norgestrel in women. Drug Metabolism and Disposition 3: 180–188 (1975b).
Skolnick, J.L.; Stoler, B.S.; Katz, D.G. and Anderson, W.H.: Rifampicin, oral contraceptives and pregnancy. Journal of the American Medical Association 236: 1382 (1976).
Smith, R.L.: Biliary excretion and hepatotoxicity of contraceptive steroids; in Briggs and Diczfalusy (Eds) Pharmacological Models in Contraceptive Development, pp. 149–168 (WHO, Stockholm 1974).
Smith, R.V.; Hassall, T.H. and Liu, S.C.: Colorimetric analysis of norethindrone, norethindrone acetate and norgestrel in oral contraceptives. Association of Official Analytical Chemists Journal 53: 1089–1092 (1970).
Somani. S.M. and Khurana, R.C.: Mechanism of estrogen-imipramine interaction. Journal of the American Medical Association 223: 560 (1973).
Speck, U.; Wendt, H.; Schulze, P.E. and Jentsch, D.: Bioavailability and pharmacokinetics of cyproterone acetate-14C and ethinyloestradiol-3H after oral administration as a coated tablet. Contraception 14: 151–163 (1976).
Spellacy, W.N.: A review of carbohydrate metabolism and the oral contraceptives. American Journal of Obstetrics and Gynecology 104: 448–460 (1969).
Stadel, B.V.; Sternthal, P.M.; Schlesselman, J.J.; Douglas, M.B.; Hall, W.D.; Kaul, L. and Ahluwalia, B.: Variation of ethinyl estradiol blood levels among healthy women using oral contraceptives. Fertility and Sterility 33: 257–260 (1980).
Stanczyk, F.Z.; Hiroi, M.; Goebelsmann, U.; Brenner, P.F.; Lumkin, M.E. and Mishell, D.R. Jr.: Radioimmunoassay of serum d-norgestrel in women following oral and intravaginal administration. Contraception 12: 279–298 (1975).
Stanczyk, F.Z.; Brenner, P.F.; Mishell, D.R.; Ortiz, A.; Gentz-chein, E.K.E. and Goebelsmann, U.: A radioimmunoassay for norethindrone (NET): Measurement of serum NET concentrations following ingestion of NET-containing oral contraceptive steroids. Contraception 18: 615–633 (1978).
Stanczyk, F.Z.; Gale, JA.; Goebelsmann, U.; Neremberg, C. and Matin, S.: Radioimmunoassay of plasma ethinyloestradiol in the presence of circulating norethindrone. Contraception 22: 457–470 (1980).
Steinetz, B.G.; Meli, A.; Giannina, T. and Beach, V.L.: Studies on biliary metabolites of orally administered ethynylestradiol (EE) and its 3-cyclopentyl ether (EECPE-quinestrol). Proceedings of the Society for Experimental Biology and Medicine 124: 1283–1289 (1967).
Stephen, K.W.; McCrossan, J.; MacKenzie, D.; MacFarlane, C.B. and Spiers, C.F.: Factors determining the passage of drugs from blood into saliva. British Journal of Clinical Pharmacology 9: 51–55 (1980).
Stillwell, W.G.; Horning, E.C.; Horning, M.G.; Stillwell. R.N. and Zlatkis, A.: Characterization of metabolites of steroid contraceptives by gas chromatography and mass spectrometry. Journal of Steroid Biochemistry 3: 699–706 (1972).
Stillwell, W.G.; Stillwell, R.N. and Horning, E.C.: Analysis of nanogram quantities of norethindrone in plasma using a GC-MS-COM selective ion detection procedure. Steroids and Lipids Research 5: 79–90 (1974).
Stimmel, G.F.; May, J.A.; Randolph, J.A. and Conn, W.M.: The metabolism of ethinyl estradiol in man. Journal of Clinical Endocrinology 11: 408–415 (1951).
Stockley, I.H.: Drug interactions: An appraisal of the current situation. Trends in Pharmacological Sciences 1: 6 (1979).
Sundaresan, G.M.; Goehl, T.J. and Prasad, V.K.: Simple high performance liquid Chromatographic assay for norethindrone-mestranol in combination tablets. Journal of Pharmaceutical Sciences 70: 702–704 (1981).
Swerdloff, R.S. and Odell, W.D.: Serum luteinizing and follicle stimulating hormone levels during sequential and nonsequential contraceptive treatment of eugonadal women. Journal of Clinical Endocrinology and Metabolism 29: 157–163 (1969).
Syvälähti, E.K.G.; Pihlajamaki, K.K. and Iisalo, E.J.: Rifampicin and drug metabolism. Lancet 2: 232–233 (1974).
Tetsuo, M.; Axelson, M. and Sjövall, J.: Selective isolation procedures for GC/MS analysis of ethinylsteroids in biological material. Journal of Steroid Biochemistry 13: 847–860 (1980).
Thomas, M.J.; Danutra, V.; Read, G.F.; Hillier, S.G. and Griffiths, K.: The detection and measurement of D-norgrestrel in human milk using sephadex LH 20 chromatography and radioimmunoassay. Steroids 30: 349–361 (1977).
Toddywalla, V.S.; Mehta, S.; Virkar, K.D. and Saxena, B.M.: Release of 19-nortestosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women. Contraception 21: 217–223 (1980).
Turkes, A.; Dyas, J.; Read, G.F. and Riad-Fahmy, D.: Enzyme immunoassay for specific determination of the synthetic estrogen, ethynyl estradiol, in plasma. Clinical Chemistry 27: 901–905 (1981).
Uniyal, J.P. and Laumas, K.R.: Binding of norgestrel to human plasma proteins. Biochimica et Biophysica Acta 427: 218–230 (1976).
Uniyal, J.P.; Buckshee, K.; Sharma, U. and Laumas, K.R.: Disappearance of [14,15-3H] d,l-norgestrel from plasma and its distribution in the reproductive tract of women. Acta Endocrinologica 82: 851–864 (1976).
Uribe, M. and Go., V.L.W.: Corticosteroid pharmacokinetics in liver disease. Clinical Pharmacokinetics 4: 233–240 (1979).
Van den Broek, J.M.; Teunissen, M.W.E. and Breimer, D.D.: Induction of hexobarbital and antipyrine metabolism by rifampicin treatment in the pig. Drug Metabolism and Disposition 9: 541–544 (1981).
Van der Molen, H.J.; Hart, P.G. and Wijmenga, H.G.: Studies with 14C-lynestrenol in normal and lactating women. Acta Endocrinologica 61: 255–274 (1969).
Van Kammen, E.; Thijssen, J.H.H.; Rademaker, B. and Schwarz, F.: The influence of hormonal contraceptives on sex hormone binding globulin (SHBG) capacity. Contraception 11: 53–59 (1975).
Verma, P.; Curry, C.; Crocker, C.; Titus-Dillon, P. and Ahluwalia, B.: A competitive protein binding radioassay for 17α-ethynylestradiol in human plasma. Clinica Chimica Acta 63: 363–368 (1975).
Verma, P.S.; Curry, C. and Ahluwalia, B.: A radioimmunoassay for norethindrone. II. Plasma levels in hypertensive and normotensive oral contraceptive users. Analytical Letters 9: 91–103 (1976).
Victor, A. and Johansson, E.D.B.: Effects of d-norgestrel induced decreases in sex hormone binding globulin capacity on the d-norgestrel levels in plasma. Contraception 16: 115–123 (1977).
Victor, A.; Edqvist, L-E.; Lindberg, P.; Elamsson, K. and Johansson, E.D.B.: Peripheral plasma levels of d-norgestrel in women after oral administration of d-norgestrel and when using intravaginal rings impregnated with dl-norgestrel. Contraception 12: 261–278 (1975).
Victor, A.; Weiner, E. and Johansson, E.D.B.: Sex hormone binding globulin. The carrier protein for d-norgestrel. Journal of Clinical Endocrinology and Metabolism 43: 244–247 (1976).
Victor, A.; Weiner, E. and Johansson, E.D.B.: Relation between sex hormone binding globulin and d-norgestrel levels in plasma. Acta Endocrinologica 86: 430–436 (1977a).
Victor, A.; Lundberg, P.O. and Johansson, E.D.B.: Induction of sex hormone binding globulin by Phenytoin. British Medical Journal 2: 934–935 (1977b).
Vose, C.W.; Butler, J.K.; Williams, B.M.; Stafford, J.E.H.; Shelton, J.R.; Rose, D.A.; Palmer, R.F.; Breckenridge, A.M.; Orme, M.L.E. and Serlin, M.J.: Bioavailability and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate. Contraception 19: 119–127 (1979).
Walls, C.; Vose, C.W.; Horth, C.E. and Palmer, R.F.: Radioimmunoassay of plasma norethisterone after ethynodiol diacetate administration. Journal of Steroid Biochemistry 8: 167–171 (1977).
Warren, R.J. and Fotherby, K.: Plasma levels of ethynylestradiol after administration of ethynylestradiol or mestranol to human subjects. Journal of Endocrinology 59: 369–370 (1973).
Warren, R.J. and Fotherby, K.: Radioimmunoassay of synthetic progestogens, norethisterone and norgestrel. Journal of Endocrinology 62: 605–618 (1974a).
Warren, R.J. and Fotherby, K.: Radioimmunoassay of ethynylestradiol. Journal of Endocrinology 63: 30P–31P (1974b).
Warren, R.J. and Fotherby, K.: Metabolism of d and l-norgestrel in humans. Arzneimittel-Forschung 25: 964–965 (1975).
Weiner, E. and Johansson, E.D.B.: Plasma levels of norethindrone after i.v. injection of 200mg norethindrone enanthate. Contraception 11: 419–425 (1975).
Weiner, E. and Johansson, E.D.B.: Plasma levels of d-norgestrel, estradiol and progesterone during treatment with silastic implants containing d-norgestrel. Contraception 14: 81–92 (1976).
Weiner, E.; Johansson, E.D.B. and Wide, L.: Inhibition of the positive feedback of oestradiol during treatment with subcutaneous implants of d-norgestrel. Contraception 13: 287–298 (1976a).
Weiner, E.; Victor, A. and Johansson, E.D.B.: Plasma levels of d-norgestrel after oral administration. Contraception 14: 563–570 (1976b).
Weintraub, H.S.; Adams, L.S.; Patrick, J.W. and McGuire, J.L.: Disposition of norgestimate in the presence and absence of ethinyloestradiol after oral administration to humans. Journal of Pharmaceutical Sciences 67: 1406–1408 (1978).
Weir, R.J.: Blood pressure in women taking oral contraceptives. American Heart Journal 92: 119–120 (1976).
Wijmenga. H.G. and Molen, Van der HJ.: Studies with 4-14C mestranol in lactating women. Acta Endocrinologica 61: 665–667 (1969).
Williams, J.G. and Williams, K.I.H.: Metabolism of [2-3H] and [4-14C] ethynylestradiol-3 methyl ether (mestranol) in women. Steroids 26: 707–720 (1975).
Williams, J.G.; Longcope, C. and Williams, K..I.H.: Metabolism of [4-3H] and [4-14C] 17α-ethynylestradiol-3 methyl ether (mestranol) by women. Steroids 25: 343–354 (1975).
Williams, K.I.H.: The metabolism of radioactive 17α-ethynylestradiol-3 methyl ether (mestranol) by women. Steroids 13: 539–544 (1969).
Williams, K.I.H.; Layne, D.S.; Hobkirk, R.; Nilsen, M. and Blahey, P.R.: Metabolism of doubly labelled ethynylestradiol-3-cyclopentyl ether in women. Steroids 9: 275–287 (1967).
Williams, M.C.; Helton, E.D. and Goldzieher, J.W.: The urinary metabolites of 17α-ethynylestradiol 9α-11∈-3H in women. Chromatographic profiling and identification of ethynyl and non ethynyl compounds. Steroids 25: 229–245 (1975).
Williams, M.C. and Goldzieher, J.W.: Chromatographic patterns of urinary ethynyl estrogen metabolites in various populations. Steroids 36: 255–282 (1980).
Zilly, W.; Breimer, D.D. and Richter, E.: Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance. European Journal of Clinical Pharmacology 9: 219–227 (1975).
Zumhoff, B.; Fishman, J. and Gallagher, T.F.: Estradiol metabolism in cirrhosis. Journal of Clinical Investigation 47: 20–25 (1968).
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Orme, M.L., Back, D.J. & Breckenridge, A.M. Clinical Pharmacokinetics of Oral Contraceptive Steroids. Clin Pharmacokinet 8, 95–136 (1983). https://doi.org/10.2165/00003088-198308020-00001
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DOI: https://doi.org/10.2165/00003088-198308020-00001