Advertisement

Pharmaceutisch Weekblad

, Volume 7, Issue 5, pp 194–201 | Cite as

The photochemical decomposition of the progestogenic 19-norsteroid, norethisterone, in aqueous medium

  • A. G. J. Sedee
  • G. M. J. Beijersbergen Van Henegouwen
  • H. De Vries
  • W. Guijt
  • C. A. G. Haasnoot
Original Articles

Abstract

Norethisterone, a contraceptive 19-norsteroid, was decomposed in aqueous medium (pH 7.4) by UV-B radiation (280-320 nm). This 4-en-3-oxo-19-norsteroid was not prone to the skeletal rearrangement reactions usually observed in steroids possessing a C10-methyl group. Under the reaction conditions applied, products were formed by addition of molecules, such as solvent molecules or a second steroid molecule, and by reduction of the double bond. The prevalence of addition type reactions may have consequences for the application of norethisterone-like steroids in subdermal contraceptive devices.

Keywords

Public Health Steroid Internal Medicine Double Bond Aqueous Medium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Williams JR, Abdel-Magid A. Photolysis of 3-oxo-Δ5(10)-steroids in alcoholic solvents and in the solid phase. Tetrahedron 1981;37:1675–7.Google Scholar
  2. 2.
    Anderson RR, Parish JA. Optical properties of human skin. In: Regan JD, Parrish JA, eds. The Science of Photo-medicine. New York: Plenum Press, 1982:147–74.Google Scholar
  3. 3.
    Wade A, ed. Martindale. The Extra Pharmacopoeia. 27th ed. London: The Pharmaceutical Press, 1977:1388.Google Scholar
  4. 4.
    Horkay I, Tamási P, Prékopa A, Dalmy L. Photodermatoses induced by oral contraceptives. Arch Dermatol Res 1975;253:53–61.PubMedGoogle Scholar
  5. 5.
    Mathison IW, Haas KL. Drug Photosensitivity. 1. Light- and photosensitivities observed during oral contraceptive therapy: a review. Obstet Gynecol Surv 1970;25:389–401.PubMedGoogle Scholar
  6. 6.
    Zaun H. Hautveränderungen unter der Einnahme hormonaler Kontrazeptiva. Med Monatsschr Pharm 1981;4:161–5.PubMedGoogle Scholar
  7. 7.
    Lebech PE, Ottesen B. Sex hormones and related compounds, including oral contraceptives. In: Dukes MNG, ed. Side Effects of Drugs Annual 7. Amsterdam: Elsevier Science Publishers BV, 1984:382–96.Google Scholar
  8. 8.
    Ranney RE. Comparative metabolism of 17α-ethynylsteroids used in oral contraceptives. J Toxicol Environm Health 1977;3:139–66.Google Scholar
  9. 9.
    Viinikka L. Radioimmunoassay of a new progestagen Org 2969. and its metabolite. J Steroid Biochem 1978;9:979–82.CrossRefPubMedGoogle Scholar
  10. 10.
    Kropp PJ. Photochemical transformations of cyclohexadienones and related compounds. In: Chapman OL, ed. Organic Photochemistry. Vol 1. New York: Marcel Dekker, Inc., 1967:1–90.Google Scholar
  11. 11.
    Jeger O, Schaffner K. On photochemical transformations of steroids. Pure Appl Chem 1970;21:247–62.PubMedGoogle Scholar
  12. 12.
    Schuster DI. Photochemical rearrangements of enones. In: De Mayo P, ed. Rearrangements in ground and exited states. New York: Academic Press, 1980:167–279. (Organic Chemistry. A Series of Monographs. Vol. 42–3)Google Scholar
  13. 13.
    Chapman OL, Weiss DS. Photochemistry of cyclic enones. In: Chapman OL, ed. Organic Photochemistry. Vol. 3. New York: Marcel Dekker Inc., 1973:197–288.Google Scholar
  14. 14.
    Sedee AGJ, Beijersbergen van Henegouwen GMJ, Guijt W, Haasnoot CAG. Structure elucidation of two isomeric steroids: photolytical and thermal reaction products from norethisterone studied by two-dimensional NMR. Pharm Weekbl [Sci] 1985;7:202–7.Google Scholar
  15. 15.
    Cornforth JW, Green DT. Iodohydrins and epoxides from olefins. J Chem Soc (C) 1970;846–9.Google Scholar
  16. 16.
    De Jongh DC, Hribar JD. The identification of some human metabolites of norgestrel, a new progestational agent. Steroids 1968;11:649–66.Google Scholar
  17. 17.
    Sedee AGJ, Beijersbergen van Henegouwen GMJ, Blaauwgeers HJA. Isolation, identification and densitometric determination of norethisterone-4β,5β-epoxide after photochemical decomposition of norethisterone. Int J Pharm 1983;15:149–58.CrossRefGoogle Scholar
  18. 18.
    Sadée W, Riegelman S, Johnson LF. On the mechanism of steroid fluorescence in sulfuric acid. Part 1. The formation of trienones. Steroids 1971;17:595–606.PubMedGoogle Scholar
  19. 19.
    Sedee AGJ, Beijersbergen van Henegouwen GMJ, Guijt W, Haasnoot CAG. Assignment of the1H and13C nuclear magnetic resonance spectra of norethisterone using two-dimensional nuclear magnetic resonance spectroscopy. J Chem Soc [Perkin 11] 1984:1755–9.Google Scholar
  20. 20.
    Sedee AGJ, Beijersbergen van Henegouwen GMJ, Guijt W, Haasnoot CAG. Conformational analysis of steroids in solution: 17β-hydroxy-19-nor-5α,17α-pregn-20-yn-3-one and its 5β-isomer studied by nuclear magnetic resonance. J Org Chem (in press).Google Scholar
  21. 21.
    Caus MJ, Cánovas A, Bonet J-J. Photochemical rearrangement of a steroidal α,β-epoxylactone. Helv Chim Acta 1980;63:473–7.CrossRefGoogle Scholar
  22. 22.
    Huppi G, Eggart G, Iwasaki S, Wehrli H, Schaffner K, Jeger O. Die Beeinflussung der photochemischen Umsetzungen von gesättigten Ketonen durch α-Substituenten. Helv Chim Acta 1966;49:1986–2001.Google Scholar
  23. 23.
    Savard K, Wotiz HW, Marcus Ph, Lemon HM. Effect of ultraviolet light on steroids during paper chromatography. J Am Chem Soc 1953;75:6327–9.CrossRefGoogle Scholar
  24. 24.
    Hamlin WE, Chulski T, Johnson RH, Wagner JG. A note on the photolytic degradation of anti-inflammatory steroids. J Am Pharm Ass 1960;49:253–5.PubMedGoogle Scholar
  25. 25.
    Graham RE, Williams PA, Kenner CT. Detection of decomposition and analytical interferences in pharmaceutical preparations containing corticosteroids. J Pharm Sci 1970;59:1152–6.PubMedGoogle Scholar
  26. 26.
    Cullen LF, Rutgers JG, Lucchesi PA, Papariello GJ. Fluorometric determination of norgestrel and structurally related steroids. J Pharm Sci 1968;57:1857–64.PubMedGoogle Scholar
  27. 27.
    Yoshida I, Asahina H, Oyabara I. Photostability of some steroid hormones. Horumon To Rinsho 1974;22:881–5 (C.A. 1974;81:147242m).PubMedGoogle Scholar
  28. 28.
    Kaminski EE, Cohn RM, McQuire JL, Carstensen JT. Light stability of norethindrone and ethinylestradiol formulated with FD & C colorants. J Pharm Sci 1979;68:368–70.PubMedGoogle Scholar
  29. 29.
    Sedee AGJ, Beijersbergen van Henegouwen GMJ. Photosensitized decomposition of contraceptive steroids: a possible explanation for the observed (photo-) allergy of the oral contraceptive pill. Arch Pharm (Weinheim) 1985;318:111–9.Google Scholar
  30. 30.
    Frimer AA, Gilinsky-Sharon P, Hameiri J, Aljadeff G. Superoxide-,tert-butoxide-, and hydroxide-mediated autoxidation of 3-oxo-Δ4-steroids in aprotic media. J Org Chem 1982;47:2818–191.CrossRefGoogle Scholar
  31. 31.
    Bellus D, Kearns DR, Schaffner K. Zur Photochemie von α,β-ungesättigten cyclischen Ketonen: Spezifische Reaktionen der n,π t*- und π,π*-Triplett-zustande vonO-Acetyl-testosteron und 10-Methyl-Δ1,9-octalon-(2). Helv Chim Acta 1969;52:971–1009.Google Scholar
  32. 32.
    Schuster DI, Nunez IM, Chan CB. The mechanism of photoreduction of cyclohexanones in isopropyl alcohol. Tetrahedron Lett 1981;22:1187–90.CrossRefGoogle Scholar
  33. 33.
    Cornell DG, Avram E, Filipescu N. Photohydration of testosterone and 4-androstene-3,17-dione in aqueous solution. Steroids 1979;33:485–94.CrossRefPubMedGoogle Scholar
  34. 34.
    Dauben WG, Shaffer GW, Vietmeyer ND. Alkylsubstitution effects in the photochemistry of 2-cyclohexenones. J Org Chem 1968;33:4061–9.Google Scholar
  35. 35.
    Ferrer V, Gomez J, Bonet J-J. A type-A rearrangement in the photolysis of a steroidal α,β-unsaturated lactone. Helv Chim Acta 1977;60:1357–60.CrossRefGoogle Scholar
  36. 36.
    Chapman OL, Sieja JB, Welstead Jr WJ. Stereospecific rearrangement of an excited triplet ketone. J Am Chem Soc 1966;88:161–2.Google Scholar
  37. 37.
    Williams JR, Moore RH, Li R, Weeks CM. Photochemistry of 11α- and 11β-hydroxy steroidal 1,4-dien-3-ones and 11α- and 11β-hydroxy steroidal bicyclo-[3.1.0]hex-3-en-2-ones in neutral and acidic media. J Org Chem 1980:45:2324–31.Google Scholar
  38. 38.
    Jacobs HJC, Havinga E. Cotton effects and conformations of skeletally isomeric saturated 3-oxo-steroids. Tetrahedron 1972;28:135–53.CrossRefGoogle Scholar
  39. 39.
    Williams IA, Bladon P. A novel photochemical addition reaction of 3-acetoxypregna-5,16-dien-20-one. Tetrahedron Lett 1964;5:257–62.CrossRefGoogle Scholar
  40. 40.
    Ramey BJ, Gardner PD. Mechanism of photochemical alcohol addition to α,β-unsaturated ketones. J Am Chem Soc 1967;89:3949–50.Google Scholar
  41. 41.
    Hart H, Chen B, Jeffares M. Stereochemistry of the photoinduced and Michael addition of methanol to seven- and eight-membered 2-cycloalkenones. The effect of methyl substituents. J Org Chem 1979;44:2722–6.Google Scholar
  42. 42.
    Nann B, Gravel D, Schorta R, Wehrli H, Schaffner K, Jeger O. Die UV-Bestrahlung von Testosteron und 3-Oxo-17β-acetoxy-Δ1,5-androstadien. Helv Chim Acta 1963;46:2473–82.CrossRefGoogle Scholar
  43. 43.
    White INH. Chemical reactivity and metabolism of norethindrone-4β,5β-epoxide by rat liver microsomesin vitro. Chem Biol Interact 1980;29:103–15.PubMedGoogle Scholar
  44. 44.
    Stiver S, Yates P. Stereospecificity in the photoisomerization of steroidal α-ketols to lactones. Tetrahedron Lett 1984;25:3289–92.CrossRefGoogle Scholar
  45. 45.
    Sedee AGJ, Beijersbergen van Henegouwen GMJ, Lusthof KJ, Lodder G. Irreversible binding of norethisterone to human serum protein induced by UV-B light. Pharm Res 1984;1267–9.Google Scholar
  46. 46.
    Kappus H, Bolt HM. Irreversible protein binding of norethisterone (norethindrone) epoxide. Steroids 1976;27:29–45.CrossRefPubMedGoogle Scholar

Copyright information

© Bohn, Scheltema & Holkema 1985

Authors and Affiliations

  • A. G. J. Sedee
    • 1
  • G. M. J. Beijersbergen Van Henegouwen
    • 1
  • H. De Vries
    • 1
  • W. Guijt
    • 2
  • C. A. G. Haasnoot
    • 2
  1. 1.Department of Pharmacochemistry, Center for Bio-Pharmaceutical SciencesState University of LeidenRA LeidenThe Netherlands
  2. 2.Laboratory of Biophysical Chemistry, Faculty of ScienceUniversity of NijmegenED NijmegenThe Netherlands

Personalised recommendations