The study of the activity of isoenzymes of cytochrome P450 for the prediction of drug-drug interactions of medicines in terms of polypharmacy
Abstract
Isozymes of cytochrome P450 enzymes are major catalyzing phase I biotransformation drugs that usually leads to the formation of hydrophilic and little active metabolites. The greatest role drugs play biotransformation CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of cytochrome P450 under the influence of drugs is an important and clinically relevant mechanism pharmacokinetics drug interactions. Study of the activity of isoenzymes of cytochrome P450 using phenotyping methods (determination of the concentration of specific substrates and metabolites thereof biological fluids) against application of drugs to predict adverse drug reactions resulting from drug-drug interactions. Promising for clinical practice is the use of phenotyping for the cytochrome P450 is not exogenous and endogenous substances (eg the ratio of cortisol / 6-beta-hydroxycortisol in urine to evaluate the activity of CYP3A4), which is the most safe and minimally invasive approach to research participants.
About the Authors
D. A. Sychev
FSBEI FPE Russian Medical Academy of Continuous Professional Education of Ministry of Healthcare of the Russian Federation
Russian Federation
Moscow
Russian Federation
Moscow
V. A. Otdelenov
FSBEI FPE Russian Medical Academy of Continuous Professional Education of Ministry of Healthcare of the Russian Federation
Russian Federation
Moscow
Russian Federation
Moscow
N. P. Denisenko
FSBEI FPE Russian Medical Academy of Continuous Professional Education of Ministry of Healthcare of the Russian Federation,
Russian Federation
Moscow
Russian Federation
Moscow
V. V. Smirnov
First Moscow State Medical University named after I.M. Sechenov; NRC Institute of Immunology FMBA of Russia
Russian Federation
Moscow
Russian Federation
Moscow
References
1. Hodgson, E. (2004). A textbook of modern toxicology, John Wiley & Sons, Inc., Retrieved from http://faculty.ksu.edu.sa/73069/Documents/Toxicology.pdf
2. Gundert-Remy U., Bernauer U., Blömeke B., Döring B., Fabian E., Goebel C., Hessel S., Jäckh C., Lampen A., Oesch F., Petzinger E., Völkel W., Roos P.H. Extrahepatic metabolism at the body’s internal-external interfaces. Drug Metab Rev. 2014 Aug;46(3):291-324.
3. Manevski N., Swart P., Balavenkatraman K.K., Bertschi B., Camenisch G., Kretz O., Schiller H., Walles M., Ling B., Wettstein R., Schaefer D.J., Itin P., Ashton-Chess J., Pognan F., Wolf A., Litherland K. Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation, N-Acetylation, Catechol Methylation, and Glutathione Conjugation. Drug Metab Dispos. 2014 Oct 22.
4. Tomlin Mark E. Pharmacology & Pharmacokinetics a Basic Reader. New York: Springer, 2010.
5. Williams J.A., Hyland R., Jones B.C., Smith D.A., Hurst S., Goosen T.C., Peterkin V., Koup J.R., Ball S.E. Drug-drug interactions for UDP-glucuronosyltransferasesubstrates: a pharmacokinetic explanation for typically observed low exposure(AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov; 32 (11): 1201–8.
6. Rendic S., Di Carlo F.J. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997 Feb-May; 29 (1–2): 413–580.
7. Pandit Nita K.,Robert P. Soltis. Introduction to the Pharmaceutical Sciences: An Integrated Approach. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins, 2012.
8. Kaminsky L.S., Zhang Z.Y. Human P450 metabolism of warfarin. Pharmacol Ther. 1997; 73 (1): 67–74.
9. Katoh M., Nakajima M., Yamazaki H., Yokoi T. Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport:comparison with the effects on CYP3A4. Pharm Res. 2000 Oct; 17(10): 1189–97.
10. Rodrigues A.D., Roberts E.M., Mulford D.J., Yao Y., Ouellet D. Oxidative metabolismof clarithromycin in the presence of human liver microsomes. Major role for thecytochrome P4503A (CYP3A) subfamily. Drug Metab Dispos. 1997 May; 25 (5): 623–30.
11. Corsini A., Bellosta S., Baetta R., Fumagalli R., Paoletti R., Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 1999 Dec; 84 (3): 413–28.
12. Heidbuchel H., Verhamme P., Alings M., Antz M., Hacke W., Oldgren J., Sinnaeve P., Camm A.J., Kirchhof P. European Heart Rhythm Association. European Heart RhythmAssociation Practical Guide on the use of new oral anticoagulants in patientswith non-valvular atrial fibrillation. Europace. 2013 May; 15 (5): 625–51.
13. Bertilsson L., Tybring G., Widen J., Chang M., Tomson T. Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol. 1997; 44 (2): 186–189.
14. Ohno M., Motojima K., Okano T., Taniguchi A. Induction of drugmetabolizingenzymes by phenobarbital in layered co-culture of a human liver cell line andendothelial cells. Biol Pharm Bull. 2009 May; 32 (5): 813–7.
15. Fleishaker J.C., Pearson L.K., Peters G.R. Phenytoin causes a rapid increase in 6beta-hydroxycortisol urinary excretion in humans--a putative measure of CYP3Ainduction. J Pharm Sci. 1995 Mar; 84 (3): 292–4.
16. Backman J.T., Olkkola K.T., Neuvonen P.J. Rifampin drastically reduces plasmaconcentrations and effects of oral midazolam. Clin Pharmacol Ther. 1996 Jan; 59 (1): 7–13.
17. Rahimi R., Abdollahi M. An update on the ability of St. John’s wort to affectthe metabolism of other drugs. Expert Opin Drug Metab Toxicol. 2012 Jun; 8 (6): 691–708.
18. Varhe A., Olkkola K.T., Neuvonen P.J. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994; 56 (6 Pt 1): 601–607.
19. Eagling V.A., Back D.J., Barry M.G. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol. 1997; 44 (2): 190–194.
20. Akiyoshi T., Ito M., Murase S., Miyazaki M., Guengerich F.P., Nakamura K., Yamamoto K., Ohtani H. Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants. Drug Metab Pharmacokinet. 2013; 28 (5): 411–5.
21. Chan A.T., Zauber A.G., Hsu M., Breazna A., Hunter D.J., Rosenstein R.B., Eagle C.J., Hawk E.T., Bertagnolli M.M. Cytochrome P450 2C9 variants influence response tocelecoxib for prevention of colorectal adenoma. Gastroenterology. 2009Jun; 136 (7): 2127–2136. e1.
22. Morin S., Loriot M.A., Poirier J.M., Tenneze L., Beaune P.H., FunckBrentano C., Jaillon P., Becquemont L. Is diclofenac a valuable CYP2C9 probe in humans? Eur JClin Pharmacol. 2001 Jan-Feb; 56 (11): 793–7.
23. Berka K., Hendrychová T., Anzenbacher P., Otyepka M. Membrane position ofibuprofen agrees with suggested access path entrance to cytochrome P450 2C9active site. J Phys Chem A. 2011 Oct 20; 115 (41): 11248–55.
24. Guo Y., Zhang Y., Wang Y., Chen X., Si D., Zhong D., Fawcett J.P., Zhou H. Role ofCYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans. Drug Metab Dispos. 2005 Jun; 33 (6): 749–53.
25. Chesné C., Guyomar C., Guillouzo A., Schmid J., Ludwig E., Sauter T. Metabolism ofMeloxicam in human liver involves cytochromes P4502C9 and 3A4. Xenobiotica. 1998 Jan; 28 (1): 113.
26. Bae J.W., Kim J.H., Choi C.I., Kim M.J., Kim H.J., Byun S.A., Chang Y.S., Jang C.G., Park Y.S., Lee S.Y. Effect of CYP2C9*3 allele on the pharmacokinetics of naproxen in Koreansubjects. Arch Pharm Res. 2009 Feb; 32 (2): 269–73.
27. Bertilsson L., Tybring G., Widen J., Chang M., Tomson T. Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Clin Pharmacol. 1997; 44 (2): 186–189.
28. Zhang Y.F., Chen X.Y., Guo Y.J., Si D.Y., Zhou H., Zhong D.F. Impact of cytochrome P450 CYP2C9 variant allele CYP2C9*3 on the pharmacokinetics of glibenclamide and lornoxicam in Chinese subjects. Yao Xue Xue Bao. 2005; 40: 796–799.
29. Niemi M., Cascorbi I., Timm R., Kroemer H.K., Neuvonen P.J., Kivisto K.T. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther. 2002; 72: 326–332.
30. Kidd R.S., Straughn A.B., Meyer M.C., Blaisdell J., Goldstein J.A., Dalton J.T. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics. 1999; 9: 71–80.
31. Kirchheiner J., Bauer S., Meineke I., Rohde W., Prang V., Meisel C., Roots I., Brockmöller J. Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kineticsand the insulin and glucose response in healthy volunteers. Pharmacogenetics. 2002 Mar; 12 (2): 101–9.
32. Chen G., Jiang S., Mao G., Zhang S., Hong X., Tang G., Li Z., Liu X., Zhang Y., Xing H.,Wang B., Yu Y., Xu X. CYP2C9 Ile359Leu polymorphism, plasma irbesartanconcentration and acute blood pressure reductions in response to irbesartantreatment in Chinese hypertensive patients. Methods Find Exp Clin Pharmacol. 2006 Jan–Feb; 28 (1): 19–24.
33. McCrea J.B., Cribb A., Rushmore T., Osborne B., Gillen L., Lo M.W., Waldman S., Bjornsson T., Spielberg S., Goldberg M.R. Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its activemetabolite E-3174. Clin Pharmacol Ther. 1999 Mar; 65 (3): 348–52.
34. Food and Drug Administration: Table of Pharmacogenomic Biomarkers in Drug Labeling. URL: http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
35. Kidd R.S., Straughn A.B., Meyer M.C., Blaisdell J., Goldstein J.A., Dalton J.T. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics. 1999; 9: 71–80.
36. Veronese M.E., Mackenzie P.I., Doecke C.J., McManus M.E., Miners J.O., Birkett D.J. Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res Commun. 1991; 175: 1112–1118.
37. Coller J.K., Krebsfaenger N., Klein K., Endrizzi K., Wolbold R., Lang T., Nüssler A., Neuhaus P., Zanger U.M., Eichelbaum M., Mürdter T.E. The influence of CYP2B6, CYP2C9and CYP2D6 genotypes on the formation of the potent antioestrogenZ-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol. 2002 Aug; 54 (2): 157–67.
38. Ekhart C., Doodeman V.D., Rodenhuis S., Smits P.H., Beijnen J.H., Huitema A.D. Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenet Genomics. 2008; 18: 515–523.
39. Griskevicius L., Yasar U., Sandberg M., Hidestrand M., Eliasson E., Tybring G., Hassan M., Dahl M.L. Bioactivation of cyclophosphamide: the role of polymorphicCYP2C enzymes. Eur J Clin Pharmacol. 2003 Jun; 59 (2): 103–9.
40. Rana R., Chen Y., Ferguson S.S., Kissling G.E., Surapureddi S., Goldstein J.A. Hepatocyte nuclear factor 4{alpha} regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes. Drug Metab Dispos. 2010 Apr; 38 (4): 591–9.
41. Kaukonen K.M., Olkkola K.T., Neuvonen P.J. Fluconazole but not itraconazoledecreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol. 1998Feb; 53 (6): 445–9.
42. Wu X., Yuan L., Zuo J., Lv J., Guo T. The impact of CYP2D6 polymorphisms on the pharmacokinetics of codeine and its metabolites in Mongolian Chinese subjects. Eur J Clin Pharmacol. 2014 Jan; 70 (1): 57–63.
43. Preskorn S.H., Shah R., Neff M., Golbeck A.L., Choi J. The potential for clinicallysignificant drug-drug interactions involving the CYP 2D6 system: effects withfluoxetine and paroxetine versus sertraline. J Psychiatr Pract. 2007 Jan; 13 (1): 5–12.
44. O’Hara G.E., Philippon F., Gilbert M., Champagne J., Michaud V., Charbonneau L., Pruneau G., Hamelin B.A., Geelen P., Turgeon J. Combined Administration of Quinidine and Propafenone for Atrial Fibrillation: The CAQ-PAF Study. J Clin Pharmacol. 2012 Feb; 52 (2): 171–9.
45. Spina E., Santoro V., D’Arrigo C. Clinically relevant pharmacokinetic druginteractions with second-generation antidepressants: an update. Clin Ther. 2008 Jul; 30 (7): 1206–27.
46. Haertter S. Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6. Drug Metabol Drug Interact. 2013; 28 (4): 209–16.
47. Rae J.M., Johnson M.D., Lippman M.E., Flockhart D.A. Rifampin is a selective,pleiotropic inducer of drug metabolism genes in human hepatocytes: studies withcDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther. 2001 Dec; 299 (3): 849–57.
48. Wadelius M., Darj E., Frenne G., Rane A. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther. 1997 Oct; 62 (4): 400–7.
49. Ayari I., Fedeli U., Saguem S., Hidar S., Khlifi S., Pavanello S. Role of CYP1A2 polymorphisms in breast cancer risk in women. Mol Med Rep. 2013 Jan; 7 (1): 280–6.
50. Fontana R.J., Lown K.S., Paine M.F., Fortlage L., Santella R.M., Felton J.S., Knize M.G.,Greenberg A., Watkins P.B. Effects of a chargrilled meat diet on expression ofCYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers. Gastroenterology. 1999 Jul; 117 (1): 89–98.
51. Hakooz N., Hamdan I. Effects of dietary broccoli on human in vivo caffeine metabolism: a pilot study on a group of Jordanian volunteers. Curr Drug Metab. 2007 Jan; 8 (1): 9–15.
52. Karjalainen M.J., Neuvonen P.J., Backman J.T. In vitro inhibition of CYP1A2 bymodel inhibitors, anti-inflammatory analgesics and female sex steroids:predictability of in vivo interactions. Basic Clin Pharmacol Toxicol. 2008 Aug; 103 (2): 157–65.
53. Rendic S. Summary of information on human CYP enzymes: human P450 metabolismdata. Drug Metab Rev. 2002 Feb-May; 34 (1–2): 83–448.
54. Ritter, James. A Textbook of Clinical Pharmacology and Therapeutics. 5th ed. London: Hodder Arnold, 2008.
55. Ingelman-Sundberg M., Sim S.C., Gomez A., Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007 Dec; 116 (3): 496–526.
56. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf
57. Michaut A., Moreau C., Robin M.A., Fromenty B. Acetaminopheninduced liver injury in obesity and nonalcoholic fatty liver disease. Liver Int. 2014 Aug; 34 (7): e171–9.
58. Tompkins L.M., Wallace A.D. Mechanisms of cytochrome P450 induction. J BiochemMol Toxicol. 2007; 21 (4): 176–81.
59. Azzalis L.A., Fonseca F.L., Simon K.A., Schindler F., Giavarotti L., Monteiro H.P., Videla L.A., Junqueira V.B. Effects of ethanol on CYP2E1 levels and relatedoxidative stress using a standard balanced diet. Drug Chem Toxicol. 2012 Jul; 35 (3): 324–9.
60. Brewer L., Williams D. Clinically Relevant Drug-Drug and Drug-Food Interactions. Pharmaceutical medicine. 2013. 27 (1): 9–23.
61. European Medicines Agency. Committee for Human Medicinal Products. Guideline on the Investigation of Drug Interactions 2012. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf
62. Сычев Д.А. Рекомендации для фармацевтических компаний по изучению биотрансформации и транспортеров новых лекарственных средств: дизайн исследований, анализ данных и внесение информации в инструкции по применению. /Науч. ред. В. Г. Кукес. М.: 2009.URL: http://www.regmed.ru/Content/Doc.aspx?id=26a9128c-ee32-4469-9c645c666339049e
63. Shin K.H., Choi M.H., Lim K.S., Yu K.S., Jang I.J., Cho J.Y. Evaluation of endogenousmetabolic markers of hepatic CYP3A activity using metabolic profiling andmidazolam clearance. Clin Pharmacol Ther. 2013 Nov; 94 (5): 601–9.
64. Yasar U., Forslund-Bergengren C., Tybring G., Dorado P., Llerena A., Sjöqvist F., Eliasson E., Dahl M.L. Pharmacokinetics of losartan and its metabolite E-3174 inrelation to the CYP2C9 genotype. Clin Pharmacol Ther. 2002 Jan; 71 (1): 89–98.
65. Stearns R.A., Chakravarty P.K., Chen R., Chiu S.H. Biotransformation of losartan toits active carboxylic acid metabolite in human liver microsomes. Role ofcytochrome P4502C and 3A subfamily members. Drug Metab Dispos. 1995 Feb; 23 (2): 207–15.
66. Yun C.H., Lee H.S., Lee H., Rho J.K., Jeong H.G., Guengerich F.P. Oxidation of theangiotensin II receptor antagonist losartan (DuP 753) in human liver microsomes.Role of cytochrome P4503A(4) in formation of the active metabolite EXP3174. DrugMetab Dispos. 1995 Feb; 23 (2): 285–9.
67. Yasar U., Tybring G., Hidestrand M., Oscarson M., Ingelman-Sundberg M., Dahl M.L., Eliasson E. Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos. 2001 Jul; 29 (7): 1051–6.
68. de Andrés F, Sosa-Macías M, Llerena A. A rapid and simple LC-MS/ MS method for the simultaneous evaluation of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4hydroxylation capacity. Bioanalysis. 2014 Mar; 6 (5): 683–96.
69. Dorado P., Gallego A., Peñas-LLedó E., Terán E., Lerena A. Relationship betweenthe CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthyEcuadorian volunteers. Pharmacogenomics. 2014 Aug; 15 (11): 1417–21.
70. Sekino K., Kubota T., Okada Y., Yamada Y., Yamamoto K., Horiuchi R., Kimura K., Iga T. Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects. Eur J Clin Pharmacol. 2003 Nov; 59 (8–9): 589–92.
71. Galteau M.M., Shamsa F. Urinary 6beta-hydroxycortisol: a validated test forevaluating drug induction or drug inhibition mediated through CYP3A in humans andin animals. Eur J Clin Pharmacol. 2003 Dec; 59 (10): 713–33.
Review
For citations:
Sychev D.A., Otdelenov V.A., Denisenko N.P., Smirnov V.V. The study of the activity of isoenzymes of cytochrome P450 for the prediction of drug-drug interactions of medicines in terms of polypharmacy. Pharmacogenetics and Pharmacogenomics. 2016;(2):4-11. (In Russ.)
Views:
2669
Email this article 
Post a Comment 