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Predicting drug–drug interactions by electrochemically driven cytochrome P450 3A4 reactions

  • Victoria V. Shumyantseva EMAIL logo , Polina I. Koroleva , Tatiana V. Bulko , Gennady V. Sergeev and Sergei A. Usanov
Published/Copyright: December 6, 2021
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Drug Metabolism and Personalized Therapy
From the journal Drug Metabolism and Personalized Therapy Volume 37 Issue 3

Abstract

Objectives

Human cytochrome P450 3A4 is the most abundant hepatic and intestinal Phase I enzyme that metabolizes approximately 60% marketed drugs. Simultaneous administration of several drugs may result in appearance of drug–drug interaction. Due to the great interest in the combination therapy, the exploration of the role of drug as “perpetrator” or “victim” is important task in pharmacology. In this work the model systems based on electrochemically driven cytochrome P450 3A4 for the analysis of drug combinations was used. We have shown that the analysis of electrochemical parameters of cytochrome P450 3A4 and especially, potential of the start of catalysis, Eonset, possess predictive properties in the determination of the leading (“perpetrator”) properties of drug. Based on these experimental data, we concluded, that the more positive potential of the start of catalysis, Eonset, the more pronounced the role of drug as leading medication.

Methods

Electrochemically driven cytochrome P450 3A4 was used as probe and measuring tool for the estimation of the role of interacting drugs.

Results

It is shown that the electrochemical non-invasive model systems for monitoring the catalytic activity of cytochrome P450 3A4 can be used as prognostic devise in assessment of drug/drug interacting medications.

Conclusions

Cytochrome P450 3A4 activity was studied in electrochemically driven system. Method was implemented to monitor drug/drug interactions. Based on the obtained experimental data, we can conclude that electrochemical parameter such as potential of onset of catalysis, Eonset, has predictive efficiency in assessment of drug/drug interacting medications in the case of the co-administration.

Keywords: cytochrome P450 3A4; diclofenac; drug–drug interactions; electrocatalysis; electrochemical parameters; erythromycin; prediction
Corresponding author: Victoria V. Shumyantseva, Institute of Biomedical Chemistry, Moscow 119121, Russia; and Pirogov Russian National Research Medical University, Moscow, Russia, E-mail:

  1. Research funding: This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital biodesign and personalized healthcare” No. 75-15-2020-913.

  2. Author contributions: All the authors have accepted responsibility for the entire of this manuscript and approved this submission.

  3. Competing interests: The funding organization played no role in the study design; in the collection, analysis and interpretation of data; in the writing of this manuscript, or in the decision to submit the manuscript for publication.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The local Institutional Review Board deemed the study exempt from review.

References

1. Jalalvand, AR. A study originated from combination of electrochemistry and chemometrics for investigation of the inhibitory effects of ciprofloxacin as a potent inhibitor on cytochrome P450. Microchem J 2020;157:105104. https://doi.org/10.1016/j.microc.2020.105104.Search in Google Scholar

2. Krishnan, S Bioelectrodes for evaluating molecular therapeutic and toxicity properties. Curr Opin Electrochem 2020;19:20–6. https://doi.org/10.1016/j.coelec.2019.09.004.Search in Google Scholar

3. Kato, H. Computational prediction of cytochrome P450 inhibition and induction. Drug Metabol Pharmacokinet 2020;35:30–44. https://doi.org/10.1016/j.dmpk.2019.11.006.Search in Google Scholar PubMed

4. Guengerich, P. In: Ortiz de Montellano, PR, editor. Cytochrome P450. Structure, mechanism, and biochemistry. San Francisco: Springer-Verlag US; 2015:523–785 pp.10.1007/978-3-319-12108-6_9Search in Google Scholar

5. Zanger, U, 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. https://doi.org/10.1016/j.pharmthera.2012.12.007.Search in Google Scholar PubMed

6. Kennedy, C, Brewer, L, Williams, D. Drug interactions. Medicine 2020;48:450–5. https://doi.org/10.1016/j.mpmed.2020.04.001.Search in Google Scholar

7. Shumyantseva, VV, Kuzikov, AV, Masamrekh, RA, Bulko, TV, Archakov, AI. From electrochemistry to enzyme kinetics of cytochrome P450. Biosens Bioelectron 2018;121:192–204. https://doi.org/10.1016/j.bios.2018.08.040.Search in Google Scholar PubMed

8. Koroleva, PI, Kuzikov, AV, Masamrekh, RA, Filimonov, DA, Dmitriev, AV, Zaviyalova, MG, et al.. Modeling of drug-drug interactions between omeprazole and erythromycin in the cytochrome P450-dependent system in vitro. Biochem (Mos), Suppl Ser B: Biomed Chem 2021;15:62–70. https://doi.org/10.1134/s1990750821010030.Search in Google Scholar

9. Shumyantseva, V, Bulko, T, Kuzikov, A, Masamrekh, R, Konyakhina, A, Romanenko, I, et al.. All-electrochemical nanocomposite two-electrode setup for quantification of drugs and study of their electrocatalytical conversion by cytochromes P450. Electrochim Acta 2020;336:135579. https://doi.org/10.1016/j.electacta.2019.135579.Search in Google Scholar

10. Masamrekh, RA, Filippova, TA, Sherbakov, KA, Veselovsky, AV, Shumyantseva, VV, Kuzikov, AV. Interactions of galeterone and its 3‐keto‐Δ4 metabolite (D4G) with one of the key enzymes of corticosteroid biosynthesis – steroid 21‐monooxygenase (CYP21A2). Fundam Clin Pharmacol 2021;35:423–31. https://doi.org/10.1111/fcp.12607.Search in Google Scholar PubMed

11. Masamrekh, RA, Kuzikov, AV, Haurychenka, YI, Shcherbakov, KA, Veselovsky, AV, Filimonov, DA, et al.. In vitro interactions of abiraterone, erythromycin, and CYP3A4: implications for drug-drug interactions. Fundam Clin Pharmacol 2020;34:120–30. https://doi.org/10.1111/fcp.12497.Search in Google Scholar PubMed

12. Makhova, AA, Shikh, EV, Bulko, TV, Gilep, AA, Usanov, SA, Shumyantseva, VV. No effect of lipoic acid on catalytic activity of cytochrome P450 3A4. Drug Metabol Personal Ther 2020;35:20200105. https://doi.org/10.1515/dmpt-2020-0105.Search in Google Scholar PubMed

13. Shumyantseva, VV, Bulko, TV, Suprun, EV, Chalenko, YM, Vagin, MY, Rudakov, YO, et al.. Electrochemical investigations of cytochrome P450. Biochim Biophys Acta 2011;1814:94–101. https://doi.org/10.1016/j.bbapap.2010.07.008.Search in Google Scholar PubMed

14. Shumyantseva, VV, Makhova, AA, Shikh, EV, Bulko, TV, Kuzikov, AV, Masamrekh, RA, et al.. Bioelectrochemical systems as technologies for studying drug interactions related to cytochrome P450. BioNanoScience 2019;9:79–86. https://doi.org/10.1007/s12668-018-0567-7.Search in Google Scholar

15. Masamrekh, R, Kuzikov, A, Veselovsky, A, Toropygin, I, Shkel, T, Strushkevich, N, et al.. Interaction of 17α-hydroxylase, 17(20)-lyase (CYP17A1) inhibitors – abiraterone and galeterone – with human sterol 14α-demethylase (CYP51A1). J Inorg Biochem 2018;186:24–33. https://doi.org/10.1016/j.jinorgbio.2018.05.010.Search in Google Scholar PubMed

16. Sadeghi, SJ, Fantuzzi, A, Gilardi, G. Breakthrough in P450 bioelectrochemistry and future perspectives. Biochim Biophys Acta 2011;1814:237–48. https://doi.org/10.1016/j.bbapap.2010.07.010.Search in Google Scholar PubMed

17. Schneider, E, Clark, DS. Cytochrome P450 (CYP) enzymes and the development of CYP biosensors. Biosens Bioelectron 2013;39:1–13. https://doi.org/10.1016/j.bios.2012.05.043.Search in Google Scholar PubMed

18. Kuzikov, A, Masamrekh, R, Shkel, T, Strushkevich, N, Gilep, A, Usanov, S, et al.. Assessment of electrocatalytic hydroxylase activity of cytochrome P450 3A4 (CYP3A4) by means of derivatization of 6β-hydroxycortisol by sulfuric acid for fluorimetric assay. Talanta 2019;196:231–6. https://doi.org/10.1016/j.talanta.2018.12.041.Search in Google Scholar PubMed

19. Kuzikov, AV, Masamrekh, RA, Filippova, TA, Haurychenka, YI, Gilep, AA, Shkel, TV, et al.. Electrochemical oxidation of estrogens as a method for CYP19A1 (aromatase) electrocatalytic activity determination. Electrochim Acta 2020;333:135539. https://doi.org/10.1016/j.electacta.2019.135539.Search in Google Scholar

20. Lutz, U, Bittner, N, Ufer, M, Lutz, W. Quantification of cortisol and 6-beta-hydroxycortisol in human urine by LC-MS/MS, and gender-specific evaluation of the metabolic ratio as biomarker of CYP3A activity. J Chromatogr B 2010;878:97–101. https://doi.org/10.1016/j.jchromb.2009.11.023.Search in Google Scholar PubMed

21. Shumyantseva, VV, Bulko, TV, Kuznetsova, GP, Samenkova, NF, Archakov, AI. Electrochemistry of cytochromes P450: analysis of current-voltage characteristics of electrodes with immobilized cytochromes P450 for the screening of substrates and inhibitors. Biochemistry (Mos) 2009;74:438–44. https://doi.org/10.1134/s0006297909040129.Search in Google Scholar PubMed

22. Kuzikov, A, Masamrekh, R, Archakov, A, Shumyantseva, V. Methods for determining of cytochrome P450 isozymes functional activity. Biochem (Mos) Supp Ser B: Biomed Chem 2018;12:220–40. https://doi.org/10.1134/s1990750818030046.Search in Google Scholar

23. Panicco, P, Castrignanò, S, Sadeghi, SJ, Nardo, GD, Gilardi, G. Engineered human CYP2C9 and its main polymorphic variants for bioelectrochemical measurements of catalytic response. Bioelectrochemistry 2021;138:107729. https://doi.org/10.1016/j.bioelechem.2020.107729.Search in Google Scholar PubMed

24. Kuzikov, AV, Dugin, NO, Stulov, SV, Shcherbinin, DS, Zharkova, MS, T YaV, et al.. Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors. Steroids 2014;88:66–71. https://doi.org/10.1016/j.steroids.2014.06.014.Search in Google Scholar PubMed

25. Li, Z, Jiang, Y, Guengerich, FP, Ma, L, Li, S, Zhang, W. Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications. J Biol Chem 2020;295:833–49. https://doi.org/10.1074/jbc.rev119.008758.Search in Google Scholar PubMed PubMed Central

26. Nardo, GD, Gilardi, G. Natural compounds as pharmaceuticals: the key role of cytochromes P450 reactivity. Trends Biochem Sci 2020;45:511–25. https://doi.org/10.1016/j.tibs.2020.03.004.Search in Google Scholar PubMed

27. Shumyantseva, V, Bulko, T, Shich, E, Makhova, A, Kuzikov, A, Archakov, A. Cytochrome P450 enzymes and electrochemistry: crosstalk with electrodes as redox partners and electron sources. In Hrycay, E, Bandiera, S, editors. Monooxygenase, peroxidase and peroxygenase properties and mechanisms of cytochrome P450. Advances in Experimental Medicine and Biology. New York City: Springer Cham; 2015, vol 851:229–46 pp.10.1007/978-3-319-16009-2_9Search in Google Scholar PubMed

28. Shumyantseva, VV, Bulko, TV, Sigolaeva, LV, Kuzikov, AV, Pogodin, PV, Archakov, AI. Molecular imprinting coupled with electrochemical analysis for plasma samples classification in acute myocardial infarction diagnostic. Biosens Bioelectron 2018;99:216–22. https://doi.org/10.1016/j.bios.2017.07.026.Search in Google Scholar PubMed

29. Ogilvie, BW, Usuki, E, Yerino, P, Parkinson, A. In Rodrigues, AD editor. In vitro approaches for studying the inhibition of drug-metabolizing enzymes and identifying the drug-metabolizing enzymes responsible for the metabolism of drugs (reaction phenotyping) with emphasis on cytochrome P450, drug–drug interactions. New York: Informa Healthcare;2008:231–358 pp.10.1201/9780429131967-7Search in Google Scholar

30. Sadeghi, SJ, Ferrero, S, Nardo, GD, Gilardi, G. Drug–drug interactions and cooperative effects detected in electrochemically driven human cytochrome P450 3A4. Bioelectrochemistry 2012;86:87-91. https://doi.org/10.1016/j.bioelechem.2012.02.010.Search in Google Scholar PubMed

31. Pechurskaya, TA, Lukashevich, OP, Gilep, AA, Usanov, SA. Engineering, expression, and purification of “soluble” human cytochrome P45017α and its functional characterization. Biochem (Mos) 2008;73:806–11. https://doi.org/10.1134/s0006297908070092.Search in Google Scholar

32. Omura, T, Sato, R. The carbon monoxide-binding pigment of liver microsomes. II. Solubilization, purification, and properties. J Biol Chem 1964;239:2379–85. https://doi.org/10.1016/s0021-9258(20)82245-5.Search in Google Scholar

33. Nash, T The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J 1953;55:416–21. https://doi.org/10.1042/bj0550416.Search in Google Scholar PubMed PubMed Central

34. Mi, L, He, F, Jiang, L, Shangguan, L, Zhang, X, Ding, T, et al.. Electrochemically-driven benzo [a] pyrene metabolism via human cytochrome P450 1A1 with reductase coated nitrogen-doped graphene nano-composites. J Electroanal Chem 2017;804:23–8. https://doi.org/10.1016/j.jelechem.2017.09.035.Search in Google Scholar

35. Bartlett, PN. Bioelectrochemistry: fundamentals, experimental techniques and applications. New York: John Wiley & Sons; 2008.10.1002/9780470753842Search in Google Scholar

36. Dmitriev, AV, Filimonov, DA, Rudik, AV, Pogodin, PV, Karasev, DA, Lagunin, AA, et al.. Drug-drug interaction prediction using PASS. SAR QSAR Environ Res 2019;30:655–64. https://doi.org/10.1080/1062936x.2019.1653966.Search in Google Scholar PubMed

37. Dmitriev, A, Filimonov, D, Lagunin, A, Karasev, D, Pogodin, P, Rudik, A, et al.. Prediction of severity of drug-drug interactions caused by enzyme inhibition and activation. Molecules 2019;24:3955–62. https://doi.org/10.3390/molecules24213955.Search in Google Scholar PubMed PubMed Central

38. Ged, C, Rouillon, JM, Pichard, L, Combalbert, J, Bressot, N, Bories, P, et al.. The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. J Clin Pharmacol 1989;28:373–87. https://doi.org/10.1111/j.1365-2125.1989.tb03516.x.Search in Google Scholar PubMed PubMed Central

39. Wang, JJ, Guo, JJ, Zhan, J, Bu, HZ, Lin, JH. An in-vitro cocktail assay for assessing compound-mediated inhibition of six major cytochrome P450 enzymes. J Pharma Anal 2014;4:270–8. https://doi.org/10.1016/j.jpha.2014.01.001.Search in Google Scholar PubMed PubMed Central

40. Salo-Ahen, OMH, Alanko, I, Bhadane, R, Bonvin, AM, Honorato, RV, Hossain, S, et al.. Molecular dynamics simulations in drug discovery and pharmaceutical development. Mol Dynam Model Simulat 2021;9:71.10.3390/pr9010071Search in Google Scholar

41. Potega, A, Zelaszczyk, D, Mazerska, Z. Electrochemical and in silico approaches for liver metabolic oxidation of antitumor-active triazoloacridinone C-1305. J Pharmac Anal 2020;10:376–84.10.1016/j.jpha.2020.03.011Search in Google Scholar PubMed PubMed Central

42. Albertolle, M, Guengerich, P. The relationships between cytochromes P450 and H2O2: production, reaction, and inhibition. J Inorg Biochem 2018;186:228–34. https://doi.org/10.1016/j.jinorgbio.2018.05.014.Search in Google Scholar PubMed PubMed Central

43. Veith, A, Moorthy, B. Role of cytochrome P450s in the generation and metabolism of reactive oxygen species. Curr Opin Toxicol 2018;7:44–51. https://doi.org/10.1016/j.cotox.2017.10.003.Search in Google Scholar PubMed PubMed Central

44. Lewis, DFV. Guide to cytochromes P450: structure and function. London: Taylor & Francis; 2001.10.1201/9781420023046Search in Google Scholar

45. Ortiz de Montellano, PR. Hydrocarbon hydroxylation by cytochrome P450 Enzymes. Chem Rev 2010;110:932−48. https://doi.org/10.1021/cr9002193.Search in Google Scholar PubMed PubMed Central

46. Baj-Rossi, C, Müller, C, von Mandach, U, De Micheli, G, Carrara, S. Faradic peaks enhanced by carbon nanotubes in microsomal cytochrome P450 electrodes. Electroanalysis 2015;27:1507–15. https://doi.org/10.1002/elan.201400726.Search in Google Scholar

47. Li, M, Li, DW, Xiu, G, Long, YT. Applications of screen-printed electrodes in current environmental analysis. Curr Opin Electrochem 2017;3:137–43. https://doi.org/10.1016/j.coelec.2017.08.016.Search in Google Scholar

48. Qian, L, Durairaj, S, Chen, A. Nanomaterial-based electrochemical sensors and biosensors for the detection of pharmaceutical compounds. Biosens Bioelectron 2021;175:112836. https://doi.org/10.1016/j.bios.2020.112836.Search in Google Scholar PubMed

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/dmpt-2021-0116).

Received: 2021-02-26
Accepted: 2021-08-31
Published Online: 2021-12-06

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/dmpt-2021-0116
Keywords for this article
cytochrome P450 3A4; diclofenac; drug–drug interactions; electrocatalysis; electrochemical parameters; erythromycin; prediction

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Genotype-based chemotherapy for patients with gastrointestinal tumors: focus on oxaliplatin, irinotecan, and fluoropyrimidines
  4. Factors influencing methotrexate and methotrexate polyglutamate in patients with rheumatoid arthritis: a systematic review of population pharmacokinetics
  5. Original Articles
  6. Predicting drug–drug interactions by electrochemically driven cytochrome P450 3A4 reactions
  7. Evaluation of the stability of furosemide in tablet form during six-month storage in spaceflight and peculiarities of its pharmacokinetics and pharmacodynamics under conditions of anti-orthostatic hypokinesia
  8. CYP450 2D6 and 2C19 genotypes in ADHD: not related with treatment resistance but with over-representation of 2C19 ultra-metabolizers
  9. The markers of the organic acidemias and their ratios in healthy neonates in Serbian population
  10. Kolaviron ameliorates chronic unpredictable mild stress-induced anxiety and depression: involvement of the HPA axis, antioxidant defense system, cholinergic, and BDNF signaling
  11. The efficacy of topical Marham-e-Akbar in chronic atopic dermatitis – an open-label interventional study
  12. In vitro metabolic biomodulation of irinotecan to increase potency and reduce dose-limiting toxicity by inhibition of SN-38 glucuronide formation
  13. Datura stramonium abrogates depression- and anxiety-like disorders in mice: possible involvement of monoaminergic pathways in its antidepressant activity
  14. Synergistic anti-cancer effects of Nigella sativa seed oil and conventional cytotoxic agent against human breast cancer
  15. Short Communication
  16. MTHFR c.665C>T guided fluoropyrimidine therapy in cancer: gender-dependent effect on dose requirements
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