Advertisement

The AAPS Journal

, 21:58 | Cite as

Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4β-Hydroxycholesterol—an Interaction Study in Healthy Volunteers

  • Caroline GjestadEmail author
  • Kristine Hole
  • Tore Haslemo
  • Ulf Diczfalusy
  • Espen Molden
Research Article

Abstract

4β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4βOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4βOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4βOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4βOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1 week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4βOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.

KEY WORDS

4β-hydroxycholesterol oxysterols CYP3A4 grapefruit juice 

Notes

Acknowledgments

We acknowledge the South-Eastern Norway Regional Health Authority for PhD funding to author C. G. Moreover, we are grateful to the Department of Medical Biochemistry at Diakonhjemmet Hospital for performing measurements of cholesterol.

Compliance with Ethical Standards

The study was approved by the Regional Committee for Medical and Health Research Ethics and the Hospital’s Research Committee, and written informed consent was obtained from all participants.

Supplementary material

12248_2019_330_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 15 kb)

References

  1. 1.
    Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103–41.CrossRefGoogle Scholar
  2. 2.
    Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.CrossRefGoogle Scholar
  3. 3.
    Tracy TS, Chaudhry AS, Prasad B, Thummel KE, Schuetz EG, Zhong XB, et al. Interindividual variability in cytochrome P450-mediated drug metabolism. Drug Metab Dispos. 2016;44:343–51.CrossRefGoogle Scholar
  4. 4.
    Diczfalusy U, Miura J, Roh HK, Mirghani RA, Sayi J, Larsson H, et al. 4β-Hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians. Pharmacogenet Genomics. 2008;18:201–8.CrossRefGoogle Scholar
  5. 5.
    Lamba V, Panetta JC, Strom S, Schuetz EG. Genetic predictors of interindividual variability in hepatic CYP3A4 expression. J Pharmacol Exp Ther. 2010;332:1088–99.CrossRefGoogle Scholar
  6. 6.
    Kotlyar M, Carson SW. Effects of obesity on the cytochrome P450 enzyme system. Int J Clin Pharmacol Ther. 1999;37:8–19.PubMedGoogle Scholar
  7. 7.
    Ulvestad M, Skottheim IB, Jakobsen GS, Bremer S, Molden E, Asberg A, et al. Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects. Clin Pharmacol Ther. 2013;93:275–82.CrossRefGoogle Scholar
  8. 8.
    Klein K, Zanger UM. Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “missing heritability” problem. Front Genet. 2013;4:12.CrossRefGoogle Scholar
  9. 9.
    Fuhr U, Jetter A, Kirchheiner J. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther. 2007;81:270–83.CrossRefGoogle Scholar
  10. 10.
    Mao J, Martin I, McLeod J, Nolan G, van Horn R, Vourvahis M, et al. Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A. Drug Metab Rev. 2017;49:18–34.CrossRefGoogle Scholar
  11. 11.
    Shin KH, Choi MH, Lim KS, Yu KS, Jang IJ, Cho JY. Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance. Clin Pharmacol Ther. 2013;94:601–9.CrossRefGoogle Scholar
  12. 12.
    Gjestad C, Haslemo T, Andreassen OA, Molden E. 4β-Hydroxycholesterol level significantly correlates with steady-state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients. Br J Clin Pharmacol. 2017;83:2398–405.CrossRefGoogle Scholar
  13. 13.
    Björkhem-Bergman L, Bäckström T, Nylén H, Rönquist-Nii Y, Bredberg E, Andersson TB, et al. Comparison of endogenous 4β-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos. 2013;41:1488–93.CrossRefGoogle Scholar
  14. 14.
    Diczfalusy U, Nylén H, Elander P, Bertilsson L. 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol. 2011;71:183–9.CrossRefGoogle Scholar
  15. 15.
    Bodin K, Bretillon L, Aden Y, Bertilsson L, Broomé U, Einarsson C, et al. Antiepileptic drugs increase plasma levels of 4β-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J Biol Chem. 2001;276:38685–9.CrossRefGoogle Scholar
  16. 16.
    Bodin K, Andersson U, Rystedt E, Ellis E, Norlin M, Pikuleva I, et al. Metabolism of 4β-hydroxycholesterol in humans. J Biol Chem. 2002;277:31534–40.CrossRefGoogle Scholar
  17. 17.
    Nitta SI, Hashimoto M, Kazuki Y, Takehara S, Suzuki H, Oshimura M, et al. Evaluation of 4β-hydroxycholesterol and 25-hydroxycholesterol as endogenous biomarkers of CYP3A4: study with CYP3A-humanized mice. AAPS J. 2018;20:61.CrossRefGoogle Scholar
  18. 18.
    Gjestad C, Huynh DK, Haslemo T, Molden E. 4β-Hydroxycholesterol correlates with dose but not steady-state concentration of carbamazepine: indication of intestinal CYP3A in biomarker formation? Br J Clin Pharmacol. 2016;81:269–76.CrossRefGoogle Scholar
  19. 19.
    Hole K, Wollmann BM, Nguyen C, Haslemo T, Molden E. Comparison of CYP3A4-inducing capacity of enzyme-inducing antiepileptic drugs using 4β-hydroxycholesterol as biomarker. Br J Clin Pharmacol. 2018;40:463–8.Google Scholar
  20. 20.
    Kanebratt KP, Diczfalusy U, Bäckström T, Sparve E, Bredberg E, Böttiger Y, et al. Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4β-hydroxycholesterol. Clin Pharmacol Ther. 2008;84:589–94.CrossRefGoogle Scholar
  21. 21.
    Lütjohann D, Marinova M, Schneider B, Oldenburg J, von Bergmann K, Bieber T, et al. 4β-Hydroxycholesterol as a marker of CYP3A4 inhibition in vivo—effects of itraconazole in man. Int J Clin Pharmacol Ther. 2009;47:709–15.CrossRefGoogle Scholar
  22. 22.
    Neuhoff S, Tucker GT. Was 4β-hydroxycholesterol ever going to be a useful marker of CYP3A4 activity? Br J Clin Pharmacol. 2018;84:1620–1.CrossRefGoogle Scholar
  23. 23.
    Tomalik-Scharte D, Lutjohann D, Doroshyenko O, Frank D, Jetter A, Fuhr U. Plasma 4β-hydroxycholesterol: an endogenous CYP3A metric? Clin Pharmacol Ther. 2009;86:147–53.CrossRefGoogle Scholar
  24. 24.
    Vanhove T, de Jonge H, de Loor H, Annaert P, Diczfalusy U, Kuypers DR. Comparative performance of oral midazolam clearance and plasma 4β-hydroxycholesterol to explain interindividual variability in tacrolimus clearance. Br J Clin Pharmacol. 2016;82:1539–49.CrossRefGoogle Scholar
  25. 25.
    DeGorter MK, Tirona RG, Schwarz UI, Choi YH, Dresser GK, Suskin N, et al. Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care. Circ Cardiovasc Genet. 2013;6:400–8.CrossRefGoogle Scholar
  26. 26.
    Dutreix C, Lorenzo S, Wang Y. Comparison of two endogenous biomarkers of CYP3A4 activity in a drug-drug interaction study between midostaurin and rifampicin. Eur J Clin Pharmacol. 2014;70:915–20.CrossRefGoogle Scholar
  27. 27.
    Björkhem-Bergman L, Bäckström T, Nylén H, Rönquist-Nii Y, Bredberg E, Andersson TB, et al. Quinine compared to 4β-hydroxycholesterol and midazolam as markers for CYP3A induction by rifampicin. Drug Metab Pharmacokinet. 2014;29:352–5.CrossRefGoogle Scholar
  28. 28.
    Russell DW. Cholesterol biosynthesis and metabolism. Cardiovasc Drugs Ther. 1992;6:103–10.CrossRefGoogle Scholar
  29. 29.
    Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos. 1994;22:947–55.PubMedGoogle Scholar
  30. 30.
    Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interactions. 1998. Br J Clin Pharmacol. 2004;58:S831–40 discussion S41–3.CrossRefGoogle Scholar
  31. 31.
    Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, et al. Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab. 2008;9:384–94.CrossRefGoogle Scholar
  32. 32.
    Uesawa Y, Abe M, Mohri K. White and colored grapefruit juice produce similar pharmacokinetic interactions. Pharmazie. 2008;63:598–600.PubMedGoogle Scholar
  33. 33.
    Dzeletovic S, Breuer O, Lund E, Diczfalusy U. Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem. 1995;225:73–80.CrossRefGoogle Scholar
  34. 34.
    Acimovic J, Lövgren-Sandblom A, Monostory K, Rozman D, Golicnik M, Lütjohann D, et al. Combined gas chromatographic/mass spectrometric analysis of cholesterol precursors and plant sterols in cultured cells. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:2081–6.CrossRefGoogle Scholar
  35. 35.
    Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, et al. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes. 2009;58:2198–210.CrossRefGoogle Scholar
  36. 36.
    Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endocrinol Metab. 2009;296:E1183–94.CrossRefGoogle Scholar
  37. 37.
    Hussain MM. Intestinal lipid absorption and lipoprotein formation. Curr Opin Lipidol. 2014;25:200–6.CrossRefGoogle Scholar
  38. 38.
    Diczfalusy U, Kanebratt KP, Bredberg E, Andersson TB, Bottiger Y, Bertilsson L. 4β-hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin. Br J Clin Pharmacol. 2009;67:38–43.CrossRefGoogle Scholar
  39. 39.
    Ramsden D, Zhou J, Tweedie DJ. Determination of a degradation constant for CYP3A4 by direct suppression of mRNA in a novel human hepatocyte model, HepatoPac. Drug Metab Dispos. 2015;43:1307–15.CrossRefGoogle Scholar
  40. 40.
    Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000;68:384–90.CrossRefGoogle Scholar
  41. 41.
    Liu C, Shang YF, Zhang XF, Zhang XG, Wang B, Wu Z, et al. Co-administration of grapefruit juice increases bioavailability of tacrolimus in liver transplant patients: a prospective study. Eur J Clin Pharmacol. 2009;65:881–5.CrossRefGoogle Scholar
  42. 42.
    Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. Br J Clin Pharmacol. 2004;57:448–55.CrossRefGoogle Scholar
  43. 43.
    Gjestad C, Haslemo T, Andreassen OA, Molden E. Gjestad et al. reply to ‘Was 4β-hydroxycholesterol ever going to be a useful marker of CYP3A4 activity?’ by Neuhoff and Tucker. Br J Clin Pharmacol. 2018;84:1624–5.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Caroline Gjestad
    • 1
    Email author
  • Kristine Hole
    • 1
  • Tore Haslemo
    • 1
  • Ulf Diczfalusy
    • 2
  • Espen Molden
    • 1
    • 3
  1. 1.Center for PsychopharmacologyDiakonhjemmet HospitalOsloNorway
  2. 2.Department of Laboratory MedicineKarolinska InstitutetHuddingeSweden
  3. 3.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway

Personalised recommendations