Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives



Contraception is recommended for female patients during ursodeoxycholic acid (UDCA) treatment for the potential teratogenic effect of this bile acid, and the aim of our study was to determine whether this treatment affects the bioavailability of ethinylestradiol (EE2).


In this double-blind, randomised study, we measured EE2 pharmacokinetics in eight healthy volunteers randomly allocated to receive oral contraceptive (30 μg EE2 and 75 μg gestodene) plus either UDCA (8–10 mg/kg per day) or placebo for 21 days during the first of three consecutive menstrual cycles. After a washout period during the second cycle, the subjects received the alternative treatment during the third menstrual cycle. Serum EE2 and UDCA were measured using radioimmunoassay and gas chromatography–mass spectrometry, respectively.


The profile for serum EE2 concentration was similar during UDCA (mean maximum serum concentration 177 pg/ml, SEM 59) and during placebo treatment (153 pg/ml, SEM 62), and mean area under the curve (AUC) was 1374 pg/h per ml (SEM 580) and 1320 pg/h per ml (SEM 551) during the two regimens, respectively. The point estimates and 90% confidence intervals of UDCA/placebo ratios for EE2 AUC and for maximum serum concentration were 1.1 (0.8–1.5) and 1.2 (1.0–1.4), respectively. Mean serum triglycerides concentration increased from 58.3 mg/dl (SEM 6.8) at enrolment to 91.4 mg/dl (SEM 10.7) during placebo (P<0.01) and to 88.6 mg/dl (SEM 13.7) during UDCA treatment (P<0.05). During UDCA treatment, serum enrichment with this bile acid and with the metabolite iso-UDCA was 29% (16%) and 3% (2%), respectively.


Co-administration with UDCA does not affect the bioavailability of EE2 in healthy volunteers, indicating that contraceptive efficacy is not affected.

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  1. 1.

    Poupon RE, Lindor KD, Cauch-Dudek K et al (1997) Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 113(3):884–890

    CAS  PubMed  Google Scholar 

  2. 2.

    Beuers U, Boyer JL, Paumgartner G (1998) Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology 28(6):1449–1453

    CAS  PubMed  Google Scholar 

  3. 3.

    Lanzini A, Northfield TC (1990) Review article: bile acid therapy. Aliment Pharmacol Ther 4(1):1–24

    CAS  Google Scholar 

  4. 4.

    Barbara L, Sama C, Morselli Labate AM et al (1987) A population study on the prevalence of gallstone disease: the Sirmione study. Hepatology 7(5):913–917

    CAS  PubMed  Google Scholar 

  5. 5.

    Kim WR, Lindor KD, Locke GR III et al (2000) Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 119(6):1631–1636

    CAS  PubMed  Google Scholar 

  6. 6.

    Fotherby K (1990) Interactions with oral contraceptives. Am J Obstet Gynecol 163(6):2153–2159

    CAS  PubMed  Google Scholar 

  7. 7.

    Bacon JF, Shenfield GM (1980) Pregnancy attributable to interaction between tetracycline and oral contraceptives. BMJ 280(6210):293

    CAS  Google Scholar 

  8. 8.

    Orme ML, Back DJ (1986) Interactions between oral contraceptive steroids and broad-spectrum antibiotics. Clin Exp Dermatol 11(4):327–331

    CAS  PubMed  Google Scholar 

  9. 9.

    Goldzieher JW (1989) Pharmacology of contraceptive steroids: a brief review. Am J Obstet Gynecol 160(5):1260–1264

    CAS  PubMed  Google Scholar 

  10. 10.

    Orme ML, Back DJ (1990) Factors affecting the enterohepatic circulation of oral contraceptive steroids. Am J Obstet Gynecol 163(6):2146–2152

    CAS  PubMed  Google Scholar 

  11. 11.

    Back DJ, Grimmer SF, Orme ML et al (1988) Evaluation of committee on safety of medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics. Br J Clin Pharmacol 25(5):527–532

    CAS  PubMed  Google Scholar 

  12. 12.

    Goldzieher JW, Brody SA (1990) Pharmacokinetics of ethinyl estradiol and mestranol. Am J Obstet Gynecol 163(6):2114–2119

    CAS  PubMed  Google Scholar 

  13. 13.

    Back DJ, Orme ML (1990) Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 18(6):472–484

    CAS  PubMed  Google Scholar 

  14. 14.

    Guengerich FP, Martin MV, Beaune PH et al (1986) Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 261(11):5051–5060

    CAS  PubMed  Google Scholar 

  15. 15.

    Guengerich FP (1990) Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs. Am J Obstet Gynecol 163(6):2159–2163

    CAS  PubMed  Google Scholar 

  16. 16.

    Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369(1):11–23

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Denison MS, Whitlock JP Jr (1995) Xenobiotic-inducible transcription of cytochrome P450 genes. J Biol Chem 270(31):18175–18178

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Maurel P (1996) In: Ioannides C (ed) Cytochrome P450, metabolic and toxicological aspects. CRC, Boca Raton pp 214–270

    Google Scholar 

  19. 19.

    Tanaka M, Nakura H, Tateishi T et al (1999) Ursodeoxycholic acid prevents hepatic cytochrome P450 isozyme reduction in rats with deoxycholic acid-induced liver injury. J Hepatol 31(2):263–270

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Chen J, Farrell GC (1996) Bile acids produce a generalized reduction of the catalytic activity of cytochromes P450 and other hepatic microsomal enzymes in vitro: relevance to drug metabolism in experimental cholestasis. J Gastroenterol Hepatol 11(9):870–877

    CAS  PubMed  Google Scholar 

  21. 21.

    Paolini M, Pozzetti L, Piazza F et al (1999) Bile acid structure and selective modulation of murine hepatic cytochrome P450-linked enzymes. Hepatology 30(3):730–739

    CAS  PubMed  Google Scholar 

  22. 22.

    Paolini M, Pozzetti L, Piazza F et al (2000) Mechanism for the prevention of cholestasis involving cytochrome P4503A overexpression. J Investig Med 48(1):49–59

    CAS  PubMed  Google Scholar 

  23. 23.

    Schuetz EG, Strom S, Yasuda K et al (2001) Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276(42):39411–39418

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Bachrach WH, Hofmann AF (1982) Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. part I. Dig Dis Sci 27(8):737–761

    CAS  PubMed  Google Scholar 

  25. 25.

    Eusufzai S, Ericsson S, Cederlund T et al (1991) Effect of ursodeoxycholic acid treatment on ileal absorption of bile acids in man as determined by the SeHCAT test. Gut 32(9):1044–1048

    CAS  PubMed  Google Scholar 

  26. 26.

    Taechakraichana N, Limpaphayom K, Ninlagarn T et al (2000) A randomized trial of oral contraceptive and hormone replacement therapy on bone mineral density and coronary heart disease risk factors in postmenopausal women. Obstet Gynecol 95(1):87–94

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Kuhnz W, Back D, Power J et al (1991) Concentration of ethinyl estradiol in the serum of 31 young women following a treatment period of 3 months with two low-dose oral contraceptives in an intraindividual cross-over design. Horm Res 36(1–2):63–69

    CAS  PubMed  Google Scholar 

  28. 28.

    Kuhnz W, Louton T, Back DJ et al (1993) Radioimmunological analysis of ethinylestradiol in human serum. Validation of the method and comparison with a gas chromatographic/mass spectrometric assay. Arzneimittelforschung 43(1):16–21

    CAS  PubMed  Google Scholar 

  29. 29.

    Marschall HU, Broome U, Einarsson C et al (2001) Isoursodeoxycholic acid: metabolism and therapeutic effects in primary biliary cirrhosis. J Lipid Res 42(5):735–742

    CAS  PubMed  Google Scholar 

  30. 30.

    Baumann A, Fuhrmeister A, Brudny-Kloppel M et al (1996) Comparative pharmacokinetics of two new steroidal estrogens and ethinylestradiol in postmenopausal women. Contraception 54(4):235–242

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Rey JM, Walter G (1998) Hypericum perforatum (St John’s wort) in depression: pest or blessing? Med J Aust 169(11–12):583–586

    CAS  PubMed  Google Scholar 

  32. 32.

    Xie W, Radominska-Pandya A, Shi Y et al (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A 98(6):3375–3380

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Staudinger JL, Goodwin B, Jones SA et al (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 98(6):3369–3374

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Marschall HU, Griffiths WJ, Gotze U et al (1994) The major metabolites of ursodeoxycholic acid in human urine are conjugated with N-acetylglucosamine. Hepatology 20(4):845–853

    CAS  PubMed  Google Scholar 

  35. 35.

    Fischer S, Neubrand M, Paumgartner G (1993) Biotransformation of orally administered ursodeoxycholic acid in man as observed in gallbladder bile, serum and urine. Eur J Clin Invest 23(1):28–36

    CAS  PubMed  Google Scholar 

  36. 36.

    Connelly PW, Stachenko S, MacLean DR et al (1999) The prevalence of hyperlipidemia in women and its association with use of oral contraceptives, sex hormone replacement therapy and nonlipid coronary artery disease risk factors. Canadian heart health surveys research group. Can J Cardiol 15(4):419–427

    CAS  PubMed  Google Scholar 

  37. 37.

    Greenlund KJ, Webber LS, Srinivasan S et al (1997) Associations of oral contraceptive use with serum lipids and lipoproteins in young women: the Bogalusa heart study. Ann Epidemiol 7(8):561–567

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Bremmelgaard A, Sjovall J (1979) Bile acid profiles in urine of patients with liver diseases. Eur J Clin Invest 9(5):341–348

    CAS  PubMed  Google Scholar 

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The study was supported by a grant from Dr. Falk Pharma GmbH, Freiburg, Germany. Serum EE2 was measured free of charge at the Department of Pharmacokinetic, Schering AG, Berlin, Germany. This study complies with the current Italian laws.

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Correspondence to Alberto Lanzini.

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Baisini, O., Benini, F., Petraglia, F. et al. Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives. Eur J Clin Pharmacol 60, 481–487 (2004). https://doi.org/10.1007/s00228-004-0796-2

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  • Ursodeoxycholic acid
  • Ethinylestradiol
  • Oral contraceptives