Advertisement

Clinical Pharmacokinetics

, Volume 58, Issue 11, pp 1373–1391 | Cite as

Phenotyping of Human CYP450 Enzymes by Endobiotics: Current Knowledge and Methodological Approaches

  • Gaëlle Magliocco
  • Aurélien Thomas
  • Jules Desmeules
  • Youssef DaaliEmail author
Review Article

Abstract

Drug response is subject to an important within- and between-individual variability owing, mainly, to pharmacokinetic and pharmacodynamic factors. Pharmacokinetics includes metabolism by cytochrome P450 (CYP450), major enzymes of phase I reactions that are responsible for the biotransformation of around 60% of the currently approved drugs. CYP450 activity and/or expression are influenced by multiple intrinsic and extrinsic factors, such as drug–drug interactions or genetic polymorphisms. Present phenotyping strategies with xenobiotics used to assess CYP450 activity could be replaced by less invasive procedures using endogenous CYP450 biomarkers. In this work, we review existing knowledge on endobiotics and their ability to characterise variability of the CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes in humans. To date, it appears that there is a lack of clinical data for the majority of the endogenous compounds described in the literature or some important limitations to allow their use in clinical practice. Additional studies are needed to fill the gap or to identify new candidates, in particular through the use of metabolomics. The use of multivariate models is also a very promising approach to enhance prediction by combining several endogenous phenotyping metrics and other covariates.

Notes

Compliance with Ethical Standards

Funding

No funding has been received for the preparation of this article.

Conflict of interest

Gaëlle Magliocco, Aurélien Thomas, Jules Desmeules and Youssef Daali have no conflicts of interest that are directly relevant to the content of this article.

References

  1. 1.
    Lin JH. Pharmacokinetic and pharmacodynamic variability: a daunting challenge in drug therapy. Curr Drug Metab. 2007;8:109–36.PubMedGoogle Scholar
  2. 2.
    Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.PubMedGoogle Scholar
  3. 3.
    Isin EM, Guengerich FP. Complex reactions catalyzed by cytochrome P450 enzymes. Biochim Biophys Acta. 2007;1770:314–29.PubMedGoogle Scholar
  4. 4.
    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.PubMedGoogle Scholar
  5. 5.
    Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116:496–526.PubMedGoogle Scholar
  6. 6.
    McGraw J, Gerhardt A, Morris TC. Opportunities and obstacles in genotypic prediction of cytochrome P450 phenotypes. Expert Opin Drug Metab Toxicol. 2018;14:659–61.PubMedGoogle Scholar
  7. 7.
    Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol. 2005;97:125–34.PubMedGoogle Scholar
  8. 8.
    Hicks JK, Swen JJ, Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. Curr Drug Metab. 2014;15:218–32.PubMedGoogle Scholar
  9. 9.
    Tanaka E, Kurata N, Yasuhara H. How useful is the ‘cocktail approach’ for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J Clin Pharm Ther. 2003;28:157–65.PubMedGoogle Scholar
  10. 10.
    Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien H-C, White N, et al. A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther. 2010;87:735–42.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt J-S, et al. Pharmacokinetic drug interaction studies with enzalutamide. Clin Pharmacokinet. 2015;54:1057–69.PubMedPubMedCentralGoogle Scholar
  12. 12.
    US FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers. 2017. Available from: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed 8 May 2019.
  13. 13.
    Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther. 2013;17:165–84.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Bosilkovska M, Samer C, Déglon J, Thomas A, Walder B, Desmeules J, et al. Evaluation of mutual drug-drug interaction within Geneva cocktail for cytochrome P450 phenotyping using innovative dried blood sampling method. Basic Clin Pharmacol Toxicol. 2016;119:284–90.PubMedGoogle Scholar
  15. 15.
    Bosilkovska M, Ing Lorenzini K, Uppugunduri CRS, Desmeules J, Daali Y, Escher M. Severe vincristine-induced neuropathic pain in a CYP3A5 nonexpressor with reduced CYP3A4/5 activity: case study. Clin Ther. 2016;38:216–20.PubMedGoogle Scholar
  16. 16.
    Bodin K, Bretillon L, Aden Y, Bertilsson L, Broomé U, Einarsson C, et al. Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J Biol Chem. 2001;276:38685–9.PubMedGoogle Scholar
  17. 17.
    Yu A-M, Idle JR, Byrd LG, Krausz KW, Küpfer A, Gonzalez FJ. Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. Pharmacogenetics. 2003;13:173–81.PubMedGoogle Scholar
  18. 18.
    Kim B, Lee J, Shin K-H, Lee S, Yu K-S, Jang I-J, et al. Identification of ω- or (ω-1)-hydroxylated medium-chain acylcarnitines as novel urinary biomarkers for CYP3A activity. Clin Pharmacol Ther. 2017;103:879–87.PubMedGoogle Scholar
  19. 19.
    Tay-Sontheimer J, Shireman LM, Beyer RP, Senn T, Witten D, Pearce RE, et al. Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics. Pharmacogenomics. 2014;15:1947–62.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Dong Y, Xiao H, Wang Q, Zhang C, Liu X, Yao N, et al. Analysis of genetic variations in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 genes using oligonucleotide microarray. Int J Clin Exp Med. 2015;8:18917–26.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim B, Moon J-Y, Choi MH, Yang HH, Lee S, Lim KS, et al. Global metabolomics and targeted steroid profiling reveal that rifampin, a strong human PXR activator, alters endogenous urinary steroid markers. J Proteome Res. 2013;12:1359–68.PubMedGoogle Scholar
  22. 22.
    Shin K-H, Ahn LY, Choi MH, Moon J-Y, Lee J, Jang I-J, et al. Urinary 6β-hydroxycortisol/cortisol ratio most highly correlates with midazolam clearance under hepatic CYP3A inhibition and induction in females: a pharmacometabolomics approach. AAPS J. 2016;18:1254–61.PubMedGoogle Scholar
  23. 23.
    Shin K-H, Choi MH, Lim KS, Yu K-S, Jang I-J, Cho J-Y. Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance. Clin Pharmacol Ther. 2013;94:601–9.PubMedGoogle Scholar
  24. 24.
    Moon J-Y, Kang SM, Lee J, Cho J-Y, Moon MH, Jang I-J, et al. GC-MS-based quantitative signatures of cytochrome P450-mediated steroid oxidation induced by rifampicin. Ther Drug Monit. 2013;35:473–84.PubMedGoogle Scholar
  25. 25.
    Lee J, Kim AH, Yi S, Lee S, Yoon SH, Yu K-S, et al. Distribution of exogenous and endogenous CYP3A markers and related factors in healthy males and females. AAPS J. 2017;19:1196–204.PubMedGoogle Scholar
  26. 26.
    Frank D, Jaehde U, Fuhr U. Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol. 2007;63:321–33.PubMedGoogle Scholar
  27. 27.
    Furuta T, Suzuki A, Mori C, Shibasaki H, Yokokawa A, Kasuya Y. Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos Biol Fate Chem. 2003;31:1283–7.PubMedGoogle Scholar
  28. 28.
    Na Takuathung M, Hanprasertpong N, Teekachunhatean S, Koonrungsesomboon N. Impact of CYP1A2 genetic polymorphisms on pharmacokinetics of antipsychotic drugs: a systematic review and meta-analysis. Acta Psychiatr Scand. 2019;139:15–25.PubMedGoogle Scholar
  29. 29.
    Perera V, Gross AS, Polasek TM, Qin Y, Rao G, Forrest A, et al. Considering CYP1A2 phenotype and genotype for optimizing the dose of olanzapine in the management of schizophrenia. Expert Opin Drug Metab Toxicol. 2013;9:1115–37.PubMedGoogle Scholar
  30. 30.
    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.PubMedGoogle Scholar
  31. 31.
    Claustrat B, Leston J. Melatonin: physiological effects in humans. Neurochirurgie. 2015;61:77–84.PubMedGoogle Scholar
  32. 32.
    Yeleswaram K, Vachharajani N, Santone K. Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. J Pineal Res. 1999;26:190–1.PubMedGoogle Scholar
  33. 33.
    Ma X, Idle JR, Krausz KW, Gonzalez FJ. Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos Biol Fate Chem. 2005;33:489–94.PubMedGoogle Scholar
  34. 34.
    Demisch K, Demisch L, Nickelsen T, Rieth R. The influence of acute and subchronic administration of various antidepressants on early morning melatonin plasma levels in healthy subjects: increases following fluvoxamine. J Neural Transm. 1987;68:257–70.PubMedGoogle Scholar
  35. 35.
    Skene DJ, Bojkowski CJ, Arendt J. Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans. Br J Clin Pharmacol. 1994;37:181–6.PubMedPubMedCentralGoogle Scholar
  36. 36.
    von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Röjdmark S. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects: an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol. 2000;56:123–7.Google Scholar
  37. 37.
    Ursing C, von Bahr C, Brismar K, Röjdmark S. Influence of cigarette smoking on melatonin levels in man. Eur J Clin Pharmacol. 2005;61:197–201.PubMedGoogle Scholar
  38. 38.
    Ursing C, Härtter S, von Bahr C, Tybring G, Bertilsson L, Röjdmark S. Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in man? J Endocrinol Invest. 2002;25:459–62.PubMedGoogle Scholar
  39. 39.
    Härtter S, Ursing C, Morita S, Tybring G, von Bahr C, Christensen M, et al. Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: a pilot study. Clin Pharmacol Ther. 2001;70:10–6.PubMedGoogle Scholar
  40. 40.
    Jackson PR, Tucker GT, Lennard MS, Woods HF. Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices. Br J Clin Pharmacol. 1986;22:541–50.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Pratt VM, Del Tredici AL, Hachad H, Ji Y, Kalman LV, Scott SA, et al. Recommendations for clinical CYP2C19 genotyping allele selection: a report of the association for molecular pathology. J Mol Diagn. 2018;20:269–76.PubMedGoogle Scholar
  42. 42.
    Pharmacogene Variation Consortium (database). 2019. Available from: https://www.pharmvar.org/. Accessed 8 May 2019.
  43. 43.
    Zeldin DC. Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem. 2001;276:36059–62.PubMedGoogle Scholar
  44. 44.
    Imig JD. Epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid on endothelial and vascular function. Adv Pharmacol San Diego Calif. 2016;77:105–41.Google Scholar
  45. 45.
    El-Sherbeni AA, El-Kadi AOS. Repurposing resveratrol and fluconazole to modulate human cytochrome P450-mediated arachidonic acid metabolism. Mol Pharm. 2016;13:1278–88.PubMedGoogle Scholar
  46. 46.
    Akasaka T, Sueta D, Arima Y, Tabata N, Takashio S, Izumiya Y, et al. CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina. Int J Cardiol Heart Vasc. 2017;15:15–20.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Honkalammi J, Niemi M, Neuvonen PJ, Backman JT. Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin Pharmacol Ther. 2011;89:579–86.PubMedGoogle Scholar
  48. 48.
    Modak AS, Klyarytska I, Kriviy V, Tsapyak T, Rabotyagova Y. The effect of proton pump inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-13C breath test in GERD patients: clinical relevance for personalized medicine. J Breath Res. 2016;10:046017.PubMedGoogle Scholar
  49. 49.
    Rebsamen MC, Desmeules J, Daali Y, Chiappe A, Diemand A, Rey C, et al. The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenom J. 2009;9:34–41.Google Scholar
  50. 50.
    Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:23–37.PubMedGoogle Scholar
  51. 51.
    Yu A, Haining RL. Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CYP2D6 and CYP3A activities? Drug Metab Dispos. 2001;29:1514–20.PubMedGoogle Scholar
  52. 52.
    Daali Y, Cherkaoui S, Doffey-Lazeyras F, Dayer P, Desmeules JA. Development and validation of a chemical hydrolysis method for dextromethorphan and dextrophan determination in urine samples: application to the assessment of CYP2D6 activity in fibromyalgia patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;861:56–63.PubMedGoogle Scholar
  53. 53.
    Bertilsson L, Alm C, De Las CC, Widen J, Edman G, Schalling D. Debrisoquine hydroxylation polymorphism and personality. Lancet. 1989;1:555.PubMedGoogle Scholar
  54. 54.
    Llerena A, Edman G, Cobaleda J, Benítez J, Schalling D, Bertilsson L. Relationship between personality and debrisoquine hydroxylation capacity. Acta Psychiatr Scand. 1993;87:23–8.PubMedGoogle Scholar
  55. 55.
    Fonne-Pfister R, Bargetzi MJ, Meyer UA. MPTP, the neurotoxin inducing Parkinson’s disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufI, P450db1) catalyzing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun. 1987;148:1144–50.PubMedGoogle Scholar
  56. 56.
    Tracy TS, Chaudhry AS, Prasad B, Thummel KE, Schuetz EG, Zhong X-B, et al. Interindividual variability in cytochrome P450-mediated drug metabolism. Drug Metab Dispos Biol Fate Chem. 2016;44:343–51.PubMedGoogle Scholar
  57. 57.
    Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95:376–82.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Cardinale GJ, Donnerer J, Finck AD, Kantrowitz JD, Oka K, Spector S. Morphine and codeine are endogenous components of human cerebrospinal fluid. Life Sci. 1987;40:301–6.PubMedGoogle Scholar
  59. 59.
    Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB. Human white blood cells synthesize morphine: CYP2D6 modulation. J Immunol Baltim Md. 1950;2005(175):7357–62.Google Scholar
  60. 60.
    Mikus G, Bochner F, Eichelbaum M, Horak P, Somogyi AA, Spector S. Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism. J Pharmacol Exp Ther. 1994;268:546–51.PubMedGoogle Scholar
  61. 61.
    Beck O, Borg S, Lundman A. Concentration of 5-methoxyindoles in the human pineal gland. J Neural Transm. 1982;54:111–6.PubMedGoogle Scholar
  62. 62.
    Kirchheiner J, Henckel H-B, Franke L, Meineke I, Tzvetkov M, Uebelhack R, et al. Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets. Pharmacogenet Genom. 2005;15:579–87.Google Scholar
  63. 63.
    Welford RWD, Vercauteren M, Trébaul A, Cattaneo C, Eckert D, Garzotti M, et al. Serotonin biosynthesis as a predictive marker of serotonin pharmacodynamics and disease-induced dysregulation. Sci Rep. 2016;6:30059.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Tang GY, Ip AK, Siu AW. Pinoline and N-acetylserotonin reduce glutamate-induced lipid peroxidation in retinal homogenates. Neurosci Lett. 2007;412:191–4.PubMedGoogle Scholar
  65. 65.
    Yu A-M, Idle JR, Herraiz T, Küpfer A, Gonzalez FJ. Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase. Pharmacogenetics. 2003;13:307–19.PubMedGoogle Scholar
  66. 66.
    Jiang X-L, Shen H-W, Yu A-M. Pinoline may be used as a probe for CYP2D6 activity. Drug Metab Dispos Biol Fate Chem. 2009;37:443–6.PubMedGoogle Scholar
  67. 67.
    Sychev DA, Zastrozhin MS, Smirnov VV, Grishina EA, Savchenko LM, Bryun EA. The correlation between CYP2D6 isoenzyme activity and haloperidol efficacy and safety profile in patients with alcohol addiction during the exacerbation of the addiction. Pharmacogenom Pers Med. 2016;9:89–95.Google Scholar
  68. 68.
    Sychev DA, Zastrozhin MS, Miroshnichenko II, Baymeeva NV, Smirnov VV, Grishina EA, et al. Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration. Drug Metab Pers Ther. 2017;32:129–36.PubMedGoogle Scholar
  69. 69.
    Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther. 2014;95:653–62.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Liu Y-T, Hao H-P, Liu C-X, Wang G-J, Xie H-G. Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab Rev. 2007;39:699–721.PubMedGoogle Scholar
  71. 71.
    Wojnowski L, Kamdem LK. Clinical implications of CYP3A polymorphisms. Expert Opin Drug Metab Toxicol. 2006;2:171–82.PubMedGoogle Scholar
  72. 72.
    Hohmann N, Haefeli WE, Mikus G. CYP3A activity: towards dose adaptation to the individual. Expert Opin Drug Metab Toxicol. 2016;12:479–97.PubMedGoogle Scholar
  73. 73.
    Thelen K, Dressman JB. Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol. 2009;61:541–58.PubMedGoogle Scholar
  74. 74.
    Galteau MM, Shamsa F. Urinary 6beta-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol. 2003;59:713–33.PubMedGoogle Scholar
  75. 75.
    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.PubMedGoogle Scholar
  76. 76.
    Ged C, Rouillon JM, Pichard L, Combalbert J, Bressot N, Bories P, et al. The increase in urinary excretion of 6 beta-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. Br J Clin Pharmacol. 1989;28:373–87.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Abel SM, Back DJ. Cortisol metabolism in vitro: III. Inhibition of microsomal 6 beta-hydroxylase and cytosolic 4-ene-reductase. J Steroid Biochem Mol Biol. 1993;46:827–32.PubMedGoogle Scholar
  78. 78.
    Peng C-C, Templeton I, Thummel KE, Davis C, Kunze KL, Isoherranen N. Evaluation of 6β-hydroxycortisol, 6β-hydroxycortisone, and a combination of the two as endogenous probes for inhibition of CYP3A4 in vivo. Clin Pharmacol Ther. 2011;89:888–95.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Chen Y-C, Gotzkowsky SK, Nafziger AN, Kulawy RW, Rocci ML, Bertino JS, et al. Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity. Br J Clin Pharmacol. 2006;62:187–95.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Shibasaki H, Hosoda K, Goto M, Suzuki A, Yokokawa A, Ishii K, et al. Intraindividual and interindividual variabilities in endogenous cortisol 6β-hydroxylation clearance as an index for in vivo CYP3A phenotyping in humans. Drug Metab Dispos Biol Fate Chem. 2013;41:475–9.PubMedGoogle Scholar
  81. 81.
    Lee C. Urinary 6βP-hydroxycortisol in humans: analysis, biological variations, and reference ranges. Clin Biochem. 1995;28:49–54.PubMedGoogle Scholar
  82. 82.
    Joellenbeck L, Qian Z, Zarba A, Groopman JD. Urinary 6 beta-hydroxycortisol/cortisol ratios measured by high-performance liquid chromatography for use as a biomarker for the human cytochrome P-450 3A4. Cancer Epidemiol Prev Biomark. 1992;1:567–72.Google Scholar
  83. 83.
    Ohno M, Yamaguchi I, Ito T, Saiki K, Yamamoto I, Azuma J. Circadian variation of the urinary 6β-hydroxycortisol to cortisol ratio that would reflect hepatic CYP3A activity. Eur J Clin Pharmacol. 2000;55:861–5.PubMedGoogle Scholar
  84. 84.
    Hu Z-Y, Zhao Y-S, Wu D, Cheng Z-N. Endogenous cortisol 6 beta-hydroxylation clearance is not an accurate probe for overall cytochrome P450 3A phenotyping in humans. Clin Chim Acta Int J Clin Chem. 2009;408:92–7.Google Scholar
  85. 85.
    Hassan R, Ameen SS, Al Maruf A, Nandini A, Tabin H, Ahmed MU, et al. Genotype-phenotype variability in human CYP3A locus in Nepalese people residing in Bangladesh. Int J Clin Pharmacol Ther. 2013;51:207–14.PubMedGoogle Scholar
  86. 86.
    Luo X, Zheng L, Cai N, Liu Q, Yang S, He X, et al. Evaluation of 6β-hydroxycortisol and 6β-hydroxycortisone as biomarkers for cytochrome P450 3A activity: insight into their predictive value for estimating oral immunosuppressant metabolism. J Pharm Sci. 2015;104:3578–86.PubMedGoogle Scholar
  87. 87.
    Kasichayanula S, Boulton DW, Luo W-L, Rodrigues AD, Yang Z, Goodenough A, et al. Validation of 4β-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects. Br J Clin Pharmacol. 2014;78:1122–34.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Luo X, Li X, Hu Z, Cheng Z. Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism. Acta Pharmacol Sin. 2009;30:1323–9.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Woolsey SJ, Beaton MD, Choi Y-H, Dresser GK, Gryn SE, Kim RB, et al. Relationships between endogenous plasma biomarkers of constitutive cytochrome P450 3A activity and single-time-point oral midazolam microdose phenotype in healthy subjects. Basic Clin Pharmacol Toxicol. 2016;118:284–91.PubMedGoogle Scholar
  90. 90.
    Seidegård J, Dahlström K, Kullberg A. Effect of grapefruit juice on urinary 6 beta-hydroxycortisol/cortisol excretion. Clin Exp Pharmacol Physiol. 1998;25:379–81.PubMedGoogle Scholar
  91. 91.
    Abel SM, Maggs JL, Back DJ, Park BK. Cortisol metabolism by human liver in vitro: I. Metabolite identification and inter-individual variability. J Steroid Biochem Mol Biol. 1992;43:713–9.PubMedGoogle Scholar
  92. 92.
    Diczfalusy U, Miura J, Roh H-K, Mirghani RA, Sayi J, Larsson H, et al. 4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians. Pharmacogenet Genom. 2008;18:201–8.Google Scholar
  93. 93.
    Gebeyehu E, Engidawork E, Bijnsdorp A, Aminy A, Diczfalusy U, Aklillu E. Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians. Pharmacogenom J. 2011;11:130–7.Google Scholar
  94. 94.
    Hole K, Gjestad C, Heitmann KM, Haslemo T, Molden E, Bremer S. Impact of genetic and nongenetic factors on interindividual variability in 4β-hydroxycholesterol concentration. Eur J Clin Pharmacol. 2017;73:317–24.PubMedGoogle Scholar
  95. 95.
    Diczfalusy U, Kanebratt KP, Bredberg E, Andersson TB, Böttiger 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.PubMedPubMedCentralGoogle Scholar
  96. 96.
    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 Biol Fate Chem. 2013;41:1488–93.PubMedGoogle Scholar
  97. 97.
    Tomalik-Scharte D, Lütjohann D, Doroshyenko O, Frank D, Jetter A, Fuhr U. Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric? Clin Pharmacol Ther. 2009;86:147–53.PubMedGoogle Scholar
  98. 98.
    Slaunwhite WR, Karsay MA, Hollmer A, Sandberg AA, Niswander K. Fetal liver as an endocrine tissue. Steroids. 1965;2:211–21.Google Scholar
  99. 99.
    Cresteil T, Beaune P, Kremers P, Flinois JP, Leroux JP. Drug-metabolizing enzymes in human foetal liver: partial resolution of multiple cytochromes P 450. Pediatr Pharmacol (N Y). 1982;2:199–207.Google Scholar
  100. 100.
    Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ, et al. Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther. 2003;307:573–82.PubMedGoogle Scholar
  101. 101.
    Miller KKM, Cai J, Ripp SL, Pierce WM, Rushmore TH, Prough RA. Stereo- and regioselectivity account for the diversity of dehydroepiandrosterone (DHEA) metabolites produced by liver microsomal cytochromes P450. Drug Metab Dispos Biol Fate Chem. 2004;32:305–13.PubMedGoogle Scholar
  102. 102.
    Nakashima T, Sano A, Seto Y, Nakajima T, Shima T, Sakamoto Y, et al. Unusual trihydroxy bile acids in the urine of patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and those with cirrhosis. Hepatology. 1990;11:255–60.PubMedGoogle Scholar
  103. 103.
    Wietholtz H, Marschall HU, Sjövall J, Matern S. Stimulation of bile acid 6 alpha-hydroxylation by rifampin. J Hepatol. 1996;24:713–8.PubMedGoogle Scholar
  104. 104.
    Back P. Phenobarbital-induced alterations of bile acid metabolism in cases of intrahepatic cholestasis. Klin Wochenschr. 1982;60:541–9.PubMedGoogle Scholar
  105. 105.
    Bodin K, Lindbom U, Diczfalusy U. Novel pathways of bile acid metabolism involving CYP3A4. Biochim Biophys Acta. 2005;1687:84–93.PubMedGoogle Scholar
  106. 106.
    Hayes MA, Li X-Q, Grönberg G, Diczfalusy U, Andersson TB. CYP3A specifically catalyzes 1β-hydroxylation of deoxycholic acid: characterization and enzymatic synthesis of a potential novel urinary biomarker for CYP3A activity. Drug Metab Dispos Biol Fate Chem. 2016;44:1480–9.PubMedGoogle Scholar
  107. 107.
    Hahn TJ, Hendin BA, Scharp CR, Boisseau VC, Haddad JG. Serum 25-hydroxycalciferol levels and bone mass in children on chronic anticonvulsant therapy. N Engl J Med. 1975;292:550–4.Google Scholar
  108. 108.
    Brodie MJ, Boobis AR, Dollery CT, Hillyard CJ, Brown DJ, MacIntyre I, et al. Rifampicin and vitamin D metabolism. Clin Pharmacol Ther. 1980;27:810–4.PubMedGoogle Scholar
  109. 109.
    Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, et al. Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest. 2005;115:177–86.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T, et al. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol Pharmacol. 2006;69:56–65.PubMedGoogle Scholar
  111. 111.
    Wang Z, Lin YS, Zheng XE, Senn T, Hashizume T, Scian M, et al. An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway. Mol Pharmacol. 2012;81:498–509.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Wang Z, Schuetz EG, Xu Y, Thummel KE. Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol. 2013;136:54–8.PubMedGoogle Scholar
  113. 113.
    Hawkes CP, Li D, Hakonarson H, Meyers KE, Thummel KE, Levine MA. CYP3A4 Induction by rifampin: an alternative pathway for vitamin D inactivation in patients with CYP24A1 mutations. J Clin Endocrinol Metab. 2017;102:1440–6.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Wang Z, Lin YS, Dickmann LJ, Poulton E-J, Eaton DL, Lampe JW, et al. Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia. J Bone Miner Res. 2013;28:1101–16.PubMedPubMedCentralGoogle Scholar
  115. 115.
    McPartland JM, Giuffrida A, King J, Skinner E, Scotter J, Musty RE. Cannabimimetic effects of osteopathic manipulative treatment. J Am Osteopath Assoc. 2005;105:283–91.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Clinical Pharmacology and ToxicologyGeneva University HospitalsGenevaSwitzerland
  2. 2.Geneva-Lausanne School of PharmacyUniversity of GenevaGenevaSwitzerland
  3. 3.Unit of ToxicologyCURMLLausanne-GenevaSwitzerland
  4. 4.Swiss Center for Applied Human ToxicologyGenevaSwitzerland
  5. 5.Faculty of Biology and Medicine, Lausanne University HospitalUniversity of LausanneLausanneSwitzerland
  6. 6.Faculty of MedicineUniversity of GenevaGenevaSwitzerland

Personalised recommendations