Possibilities of predictive toxicology in assessing the potential hepatotoxicity of medicinal substances
https://doi.org/10.52419/issn2782-6252.2022.1.64
Abstract
Currently, one of the "gold" standards for determining the potential toxicity of drugs is highly informative preventive screening (HCS). This method has become a powerful tool for the evaluation of molecular, cellular and tissue toxicity, especially in the field of predictive toxicology, aimed at predicting unwanted drug-related substances. It is critical for the pharmaceutical industry to identify and subsequently mitigate potential safety risks early in the R&D process and thus reduce toxicity and the safety-related shrinkage of drug development programs. In this article, we review some of the most common used HCS assays for predictive toxicology in the pharmaceutical industry. PubMed, Elsevier Science (Scopus), and Clarivate Analytics (Web of Science) research databases were searched for original research to identify the hallmarks of the HCS methodology. Hepatotoxicity is one of the most common causes of safety and toxicity related downsizing of potential drugs in the pharmaceutical industry, as well as drug withdrawals. Hepatotoxic substances are associated with xenobiotics, drugs, substances of natural origin and chemical agents that constitute an important cause of hepatic action. A single classification based on the mechanisms of toxicity makes it possible to distinguish between intrinsic hepatotoxicity (preliminary and dose-dependent) and idiosyncratic hepatotoxicity (invisible, non-mediated immune and metabolic reactions). HCS analyzes are not intended to replace animal testing because they cannot capture the full complexity of an organism. However, they can reduce the amount of animal testing by early detection of hazards and complement animal testing. Through early identification of safety risks and optimization of chemistry series across relevant safety endpoints, HCS assays for predictive toxicology hold the promise of enhancing the successful selection of new drug candidates with satisfactory toxicological properties.
About the Authors
V. S. Ponamarev
St. Petersburg State University of Veterinary Medicine
Russian Federation
Russian Federation
A. M. Lunegov
St. Petersburg State University of Veterinary Medicine
Russian Federation
Russian Federation
References
1. An in silico model for predicting drug-induced hepatotoxicity / S. He, T. Ye, R. Wang [et al.] // International Journal of Molecular Sciences. – 2019. – Vol. 20. – No 8. – P. 1897. – DOI 10.3390/ijms20081897.
2. Bhilare, N. V. Phenolic acid-tethered isoniazid for abrogation of drug-induced hepatotoxicity: Design, synthesis, kinetics and pharmacological evaluation / N. V. Bhilare, S. S. Dhaneshwar, K. R. Mahadik // Drug Delivery and Translational Research. – 2018. – Vol. 8. – No 3. – P. 770-779. – DOI 10.1007/s13346-018-0500-1.
3. Bunchorntavakul, C. Drug Hepatotoxicity: Newer Agents / C. Bunchorntavakul, K. R. Reddy // Clinics in Liver Disease. – 2017. – Vol. 21. – No 1. – P. 115-134. – DOI 10.1016/j.cld.2016.08.009.
4. Experimental justification choise to prevent hepatotoxic reactions to anti-TB drugs based on gene-phenotypic characteristics / A. Kazakov, G. Mozhokina, Y. Zyuzya, L. Petrova // European Respiratory Journal, Supplement. – 2019. – Vol. 54. – No S63. – P. 3010. – DOI 10.1183/13993003.congress-2019.PA3010.
5. Lee, W. M. Drug-Induced Hepatotoxicity / W. M. Lee // New England Journal of Medicine. – 2003. – Vol. 349. – No 5. – P. 474.
6. Lieber, Ch. S. Interaction of ethanol with drugs, hepatotoxic agents, carcinogens and vitamins / Ch. S. Lieber // Alcohol and Alcoholism. – 1990. – Vol. 25. – No 2-3. – P. 157.
7. Moody, D. E. The effect of tetrahydrofuran on biological systems: Does a hepatotoxic potential exist? / D. E. Moody // Drug and Chemical Toxicology. – 1991. – Vol. 14. – No 4. – P. 319-342. – DOI 10.3109/01480549109011637.
8. Morales M, L. Hepatotoxicity: A drug-induced cholestatic pattern / L. Morales M, N. Vélez L, O. G. Muñoz M // Revista Colombiana de Gastroenterologia. – 2016. – Vol. 31. – No 1. – P. 36-47. – DOI 10.22516/25007440.71.
9. Smith, L. W. Plant sources of hepatotoxic pyrrolizidine alkaloids / L. W. Smith, C. C. J. Culvenor // Journal of Natural Products (Lloydia). – 1981. – Vol. 44. – No 2. – P. 129-152. – DOI 10.1021/np50014a001.
10. The role of metabolic activation in drug-induced hepatotoxicity / B. K. Park, N. R. Kitteringham, J. L. Maggs [et al.] // Annual Review of Pharmacology and Toxicology. – 2005. – Vol. 45. – P. 177-202. – DOI 10.1146/annurev.pharmtox.45.120403.100058.
11. The use of cultured hepatocytes to investigate the mechanisms of drug hepatotoxicity / J. V. Castell, M. J. Gomez-Lechon, X. Ponsoda, R. Bort // Cell Biology and Toxicology. – 1997. – Vol. 13. – No 4-5. – P. 331-338.
12. Kazyulin, A. N. Drug-induced hepatotoxicity in clinical practice / A. N. Kazyulin, E. V. Pereyaslova // Medical Council. - 2012. - No. 9. - P. 37-44.
13. Krylova, I. N. Mechanisms of hepatotoxic action of drugs / I. N. Krylova, E. G. Tsublova // Experimental and clinical pharmacology. - 2020. - T. 83. - No. 10. - S. 26-32. – DOI 10.30906/0869-2092-2020-83-10-26-32.
14. Myshkin, V. A. Hepatotoxic substances and current trends in the correction of hepatotoxic action / V. A. Myshkin, A. B. Bakirov, E. F. Repina // Medical Bulletin of Bashkortostan. - 2011. - T. 6. - No. 6. - S. 131-136.
15. Patent No. 2601919 C1 Russian Federation, IPC A61K 36/21, A61K 9/28, A61P 43/00. Method for correcting hepatotoxic reactions induced by isoniazid : No. 2015134657/15 : Appl. 08/18/2015 : publ. 11/10/2016 / E.N. Muzalevskaya, V. A. Nikolaevsky, Yu. N. Chernov; the applicant is the federal state budgetary institution of higher professional education "Voronezh State University" (FGBU VPO VGU).
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For citations:
Ponamarev V.S., Lunegov A.M. Possibilities of predictive toxicology in assessing the potential hepatotoxicity of medicinal substances. Legal regulation in veterinary medicine. 2022;(1):64-67. (In Russ.) https://doi.org/10.52419/issn2782-6252.2022.1.64
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