Advertisement

Accumulation of norethindrone and individual metabolites in human plasma during short- and long-term administration of a contraceptive dosage

  • Author Footnotes
    * Present address: Department of Pharmacology, Michigan State University, East Lansing, Michigan 48824
    W.E. Braselton Jr.
    Footnotes
    * Present address: Department of Pharmacology, Michigan State University, East Lansing, Michigan 48824
    Affiliations
    Department of Endocrinology, Medical College of Georgia, Augusta, Georgia, USA

    Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, USA

    the Center for Population Studies, Medical College of Georgia, Augusta, Georgia, USA
    Search for articles by this author
  • Author Footnotes
    ** Present address: Medical Center of Central Georgia, 777 Hemlock Street, Box 6000, Macon, Georgia 31208
    T.J. Lin
    Footnotes
    ** Present address: Medical Center of Central Georgia, 777 Hemlock Street, Box 6000, Macon, Georgia 31208
    Affiliations
    Department of Endocrinology, Medical College of Georgia, Augusta, Georgia, USA

    Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, USA

    the Center for Population Studies, Medical College of Georgia, Augusta, Georgia, USA
    Search for articles by this author
  • J.O. Ellegood
    Affiliations
    Department of Endocrinology, Medical College of Georgia, Augusta, Georgia, USA

    Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, USA

    the Center for Population Studies, Medical College of Georgia, Augusta, Georgia, USA
    Search for articles by this author
  • T.M. Mills
    Correspondence
    Reprint requests: Dr. T. M. Mills, Department of Endocrinology, Medical College of Georgia, Augusta, Georgia 30902.
    Affiliations
    Department of Endocrinology, Medical College of Georgia, Augusta, Georgia, USA

    Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, USA

    the Center for Population Studies, Medical College of Georgia, Augusta, Georgia, USA
    Search for articles by this author
  • V.B. Mahesh
    Affiliations
    Department of Endocrinology, Medical College of Georgia, Augusta, Georgia, USA

    Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, USA

    the Center for Population Studies, Medical College of Georgia, Augusta, Georgia, USA
    Search for articles by this author
  • Author Footnotes
    * Present address: Department of Pharmacology, Michigan State University, East Lansing, Michigan 48824
    ** Present address: Medical Center of Central Georgia, 777 Hemlock Street, Box 6000, Macon, Georgia 31208
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Blood levels of free, sulfate, and glucuronide conjugates of norethindrone (NE) and its ring A reduced metabolites 17α-ethynyl-5β-estrane-3α, 17β-diol and 17α-ethynyl-5α-estrane-3α, 17β-diol were measured in a female volunteer who received six consecutive daily doses of 2.5 mg. of NE and in four female volunteers undergoing chronic treatment with Orthonovum 2 mg. (2 mg. of NE and 0.1 mg. of mestranol [ME]). The blood levels were quantified by gas chromatograph-mass spectrometry. During treatment for 6 days with 2.5 mg. of NE daily, the 3 hour blood levels of NE and the ring A reduced metabolites increased in a stepwise fashion. During long-term treatment the concentrations of NE, NE sulfate, and the conjugates of the ring A reduced metabolites were seen to build up to a peak at approximately the midpoint of the treatment phase of each cycle, and drop to near baseline during the time when no drug was administered. Individuals varied as to their tendency to accumulate the drug and metabolites, and as to the relative proportion of metabolites formed.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      Reference

        • Mills T.M.
        • Lin T.J.
        • Hernandez-Ayup S.
        • Greenblatt R.B.
        • Ellegood J.O.
        • Mahesh V.B.
        The metabolic clearance rate and urinary excretion of oral contraceptive drugs. I. Norethindrone.
        Am. J. Obstet. Gynecol. 1974; 120: 764
        • Mills T.M.
        • Lin T.J.
        • Hernandez-Ayup S.
        • Greenblatt R.B.
        • Ellegood J.O.
        • Mahesh V.B.
        The metabolic clearance rate and urinary excretion of oral contraceptive drugs. II. Mestranol.
        Am. J. Obstet. Gynecol. 1974; 120: 773
        • Mills T.M.
        • Lin T.J.
        • Braselton W.E.
        • Ellegood J.O.
        • Mahesh V.B.
        Metabolism of oral contraceptive drugs. The formation and disappearance of metabolites of norethindrone and mestranol after intravenous and oral administration.
        Am. J. Obstet. Gynecol. 1976; 126: 987
        • Mahesh V.B.
        • Mills T.M.
        • Lin T.J.
        • Ellegood J.O.
        • Braselton W.E.
        Metabolism, metabolic clearance rate, blood metabolites and blood half-life of norethindrone and mestranol.
        in: Garattini S. Berendes H.W. Pharmacology of Steroid Contraceptive Drugs. Raven Press, New York1977: 117
        • Braselton W.E.
        • Lin T.J.
        • Mills T.M.
        • Ellegood J.O.
        • Mahesh V.B.
        Identification and measurement by gas chromatography-mass spectrometry of norethindrone and metabolites in human urine and blood.
        J. Steroid Biochem. 1977; 8: 9
        • Thijssen J.H.H.
        The metabolism of orally active synthetic progestational compounds.
        in: Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. 2. Pergamon Press, Ltd., Exeter1972: 217
        • Gerhards E.
        • Hecker W.
        • Hitze H.
        • Nieuweboer B.
        • Bellmann O.
        Zum Stoffwechsel von Norethisteron (17α-äthinyl-4-östren-17β-ol-3-on) unddl-sowied-Norgestrel (18-methyl-17α-äthinyl-4-östren-17β-ol-3-on) beim Menschen.
        Acta Endocrinol. 1971; 68: 219
        • Cook C.E.
        • Twine M.E.
        • Tallent C.R.
        • Wall M.E.
        • Bressler R.C.
        Norethynodrel metabolites in human plasma and urine.
        J. Pharmacol. Exp. Ther. 1972; 183: 197
        • Cook C.E.
        • Karim A.
        • Forth J.
        • Wall M.E.
        • Ranney R.E.
        • Bressler R.C.
        Ethynodiol diacetate metabolites in human plasma.
        J. Pharmacol. Exp. Ther. 1973; 185: 696
        • Sisenwine S.F.
        • Kimmel H.B.
        • Liu A.L.
        • Ruelius H.W.
        The presence ofdl-,d-, andl-norgestrel and their metabolites in the plasma of women.
        Contraception. 1975; 12: 339
        • Nygren K.G.
        • Lindberg P.
        • Martinsson K.
        • Bosu W.T.K.
        • Johansson E.D.B.
        Radioimmunoassay of norethindrone: Peripheral plasma levels after oral administration to humans and rhesus monkeys.
        Contraception. 1974; 9: 265
        • Warren R.J.
        • Fotherby K.
        Radioimmunoassay of synthetic progestogens, norethisterone and norgestrel.
        J. Endocrinol. 1974; 62: 605
        • Pasqualini J.R.
        • Castellet R.
        • Portois M.C.
        • Hill J.L.
        • Kincl F.A.
        • Cortes-Prieto J.
        Radioimmunoassay of norethindrone (17α-ethynyl-17β-hydroxy-4-estren-3-one) and ethynyl estradiol (17α-ethynyl-1,3,5 (10)-estratriene-3,17β-diol). Application to human plasma determination of norethindrone after oral administration of this steroid.
        Reproduction. 1975; 2: 197
        • Weiner E.
        • Victor A.
        • Johansson E.D.B.
        Plasma levels of d-norgestrel after oral administration.
        Contraception. 1976; 14: 563
        • Adlercrentz H.
        • Martin F.
        • Wahlroos O.
        • Soini E.
        Mass spectrometric and mass fragmentographic determination of natural and synthetic steroids in biological fluids.
        J. Steroid Biochem. 1975; 6: 247
        • Victor A.
        • Weiner E.
        • Johansson E.D.B.
        Sex hormone binding globulin: The carrier protein ford-norgestrel.
        J. Clin. Endocrinol. Metab. 1976; 43: 244