Русский
Dependence of pharmacokinetics and hepatotoxic action of isoniazid on its acetylation rate in patients with drug-sensitive pulmonary tuberculosis
DOI: https://dx.doi.org/10.18565/therapy.2022.4.41-48
Krasnova N.M., Nikolaev V.M., Efremova E.N., Egorova A.A., Tatarinova T.E., Maksimova N.E., Prokopev E.S., Kravchenko A.F., Tatarinova O.V., Vengerovsky A.I., Sychev D.A.
1) M.K. Ammosov North-Eastern Federal University, Medical Institute, Yakutsk; 2) Yakutsk Scientific Center for Complex Medical Problems; 3) E.N. Andreev Phthisiology Research and Practice Center, Yakutsk; 4) Republican Clinical Hospital No. 3, Yakutsk; 5) Siberian State Medical University of the Ministry of Healthcare, Tomsk; 6) Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow
Aim: study the effect of NAT2-mediated isoniazid acetylation rate on isoniazid pharmacokinetics and on the risk of hepatotoxic reactions during chemotherapy for pulmonary TB in patients living as residents in the Sakha Republic (Yakutia).
Material and methods. Pharmacogenetic study comprised 146 patients with newly diagnosed pulmonary TB. Genotyping was performed using real-time PCR; the following single-nucleotide polymorphisms (SNP) were included to analysis: rs1801280, rs1799930, rs1799931, rs1799929, rs1208, rs1041983. Hepatotoxicity was established based on findings of clinical laboratory monitoring using the criteria proposed by the EASL (2019). Isoniazid pharmacokinetic parameters were assessed in 35 patients. Serum isoniazid concentrations were determined using «Milikhrom-A02» high performance liquid microcolumn chromatograph, in gradient mode.
Results. Probability of liver injury (frequency of hepatotoxic reactions) in slow acetylators was higher by a factor of 8,57 compared to rapid acetylators (OR=8,57; 95% СI: 2,92–25,18). Steady state concentration (Cav) was 2.5 times higher in slow acetylators than in intermediate acetylators (p=0,0066), and 3,5 times higher than in rapid acetylators (p=0,0073).
Conclusion. Slow acetylator type was a meaningful predictor of hepatotoxic reactions in patients with drug-sensitive pulmonary TB undergoing chemotherapy with isoniazid in standard doses. Highly variable individual isoniazid pharmacokinetic parameters depended on acetylation rate of isoniazid. Determination of acetylation phenotype and isoniazid pharmacokinetic parameters are advised during chemotherapy for pulmonary TB.
Literature
1. Khan S., Mandal R.K., Elasbali A.M. et al. Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: Trial sequence meta-analysis as evidence. Biosci Rep. 2019; 39(1): BSR20180845. https://dx.doi.org/10.1042/BSR20180845. 2. Rens N.E., Uyl-de Groot C.A., Goldhaber-Fiebert J.D. et al. Cost-effectiveness of a pharmacogenomic test for stratified isoniazid dosing in treatment of active tuberculosis. Clin Infect Dis. 2020; 6: ciz1212. https://dx.doi.org/10.1093/cid/ciz1212. 3. Imam F., Sharma M., Khayyam K.U. et al. Determination of isoniazid acetylation patterns in tuberculosis patients receiving DOT therapy under the Revised National tuberculosis Control Program (RNTCP) in India. Saudi Pharm J. 2020; 28(6): 641–47. https://dx.doi.org/10.1016/j.jsps.2020.04.003. 4. Jarrar Y.B., Balasmeh A.A., Jarrar W. Sequence analysis of the N-acetyltransferase 2 gene (NAT2) among Jordanian volunteers. Libyan J Med. 2018; 13(1): 1408381. https://dx.doi.org/10.1080/19932820.2017.1408381. 5. Suvichapanich S., Fukunaga K., Zahroh H. et al. NAT2 ultraslow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis. Pharmacogenet Genomics. 2018; 28(7): 167–76. https://dx.doi.org/10.1097/FPC.0000000000000339. 6. Zhang M., Wang S., Wilffert B. et al. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: A systematic review and meta-analysis. Br J Clin Pharmacol. 2018; 84(12): 2747–60. https://dx.doi.org/10.1111/bcp.13722. 7. Metushi I., Uetrecht J., Phillips E. Mechanism of isoniazid-induced hepatotoxicity: then and now.Br J Clin Pharmacol. 2016; 81(6): 1030–36. https://dx.doi.org/10.1111/bcp.12885. 8. Wang P., Pradhan K., Zhong X-bo, Ma X. Isoniazid metabolism and hepatotoxicity. Acta Pharm. 2016; 6(5): 384–92. https://dx.doi.org/10.1016/j.apsb.2016.07.014. 9. Mthiyane T., Millard J., Adamson J. et al. N-acetyltransferase 2 genotypes among Zulu-speaking South Africans and isoniazid and N-acetyl-isoniazid pharmacokinetics during antituberculosis treatment. Antimicrob Agents Chemother. 2020; 64(4): e02376-19. https://dx.doi.org/10.1128/AAC.02376-19. 10. Human NAT2 Alleles (Haplotypes). URL: http://nat.mbg.duth.gr/Human%20NAT2%20alleles_2013.htm (date of access – 04.04.2022). 11. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019; 70(6): 1222–61. https://dx.doi.org/10.1016/j.jhep.2019.02.014. 12. Наследов А.Д. Профессиональный статистический анализ данных. С.-Пб: Питер. 2011: 400 с. [Nasledov A.D. Professional statistical data analysis. Saint Petersburg: Piter. 2011: 400 pp. (In Russ.)]. ISBN: 978-5-459-00344-4. 13. Kwon B.S., Kim Y., Lee S.H. et al. The high incidence of severe adverse events due to pyrazinamide in elderly patients with tuberculosis. PLoS One. 2020; 15(7): e0236109. https://dx.doi.org/10.1371/journal.pone.0236109. 14. Краснова Н.М., Евдокимова Н.Е., Егорова А.А. с соавт. Влияние типа ацетилирования на частоту гепатотоксичности изониазида у пациентов с впервые выявленным туберкулезом органов дыхания. Антибиотики и химиотерапия. 2020; 7–8: 31–36. [Krasnova N.M., Evdokimova N.E., Egorova A.A. et al. Influence of the acetylation type on the incidence of isoniazid-induced hepatotoxicity in patients with newly diagnosed pulmonary tuberculosis. Antibiotiki i khimioterapiya = Antibiotics and Chemotherapy. 2020; 7–8: 31–36 (In Russ.)]. https://dx.doi.org/10.37489/0235-2990-2020-65-7-8-31-36. 15. Качанова А.А., Пименова Ю.А., Шуев Г.Н. с соавт. Изучение влияния полиморфных маркеров гена NAT2 на риск развития нежелательных реакций у пациентов с легочными формами туберкулеза, получавших изониазид и рифампицин. Безопасность и риск фармакотерапии. 2021; 1: 25–33. [Kachanova A.A., Pimenova Yu.A., Shuev G.N. et al. Study of the effect of polymorphic markers of the NAT2 gene on the risk of adverse drug reactions in patients with pulmonary tuberculosis who received isoniazid and rifampicin. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2021; 1: 25–33 (In Russ.)]. https://dx.doi.org/10.30895/2312-7821-2021-9-1-25-33. 16. Combrink M., Loots D.T., du Preez I. Metabolomics describes previously unknown toxicity mechanisms of isoniazid and rifampicin. Toxicol Lett. 2020; 322: 104–10. https://dx.doi.org/10.1016/j.toxlet.2020.01.018. 17. Jung J.A., Kim T.E., Lee H. et al. A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis. Drug Des Devel Ther. 2015; 9: 5433–38. https://dx.doi.org/10.2147/DDDT.S87131. 18. Park J.S., Lee J.Y., Lee Y.J. et al. Serum levels of antituberculosis drugs and their effect on tuberculosis treatment outcome. Antimicrob Agents Chemother. 2015; 60(1): 92–98. https://dx.doi.org/10.1128/AAC.00693-15. 19. Erwin E.R., Addison A.P., John S.F. et al. Pharmacokinetics of isoniazid: The good, the bad, and the alternatives. Tuberculosis (Edinb). 2019; 116S: S66–S70. https://dx.doi.org/10.1016/j.tube.2019.04.012. 20. Pasipanodya J.G., McIlleron H., Burger A. et al. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis. 2013; 208(9): 1464–73. https://dx.doi.org/10.1093/infdis/jit352. 21. Sileshi T., Tadesse E., Makonnen E. et al. The impact of first-line anti-tubercular drugs’ pharmacokinetics on treatment outcome: A systematic review. Clin Pharmacol. 2021; 13: 1–12. https://dx.doi.org/10.2147/CPAA.S289714.
About the Autors
Natalia M. Krasnova, PhD in Medicine, associate professor of the Department «Hospital Therapy, Occupational Diseases and Clinical Pharmacology», Medical Institute of M.K. Ammosov North-Eastern Federal University. Address: 677013, Yakutsk, 27 Oyunskogo Str. E-mail: krasnova14@mail.ru. ORCID: https://orcid.org/0000-0002-4811-7801
Vyacheslav M. Nikolaev, PhD in Biology, senior researcher at the Department of epidemiology of chronic noncommunicable diseases, Yakutsk Scientific Center for Complex Medical Problems. Address: 677019, Yakutsk, 4 Sergelyakhskoe Highway. E-mail: nikolaev1126@mail.ru. ORCID: https://orcid.org/0000-0003-4490-8910
Efrosinya N. Efremova, phthisiatrician at the Department of patients with tuberculosis of the respiratory organs, E.N. Andreev Phthisiology Research and Practice Center. Address: 677015, Yakutsk, 93 Petra Alekseeva Str. E-mail: efremovaen@tub.ykt.ru
Alexandra A. Egorova, phthisiatrician at the Department of patients with tuberculosis of the respiratory organs, E.N. Andreev Phthisiology Research and Practice Center. Address: 677015, Yakutsk, 93 Petra Alekseeva Str. E-mail: egorovaaa@tub.ykt.ru
Tatyana E. Tatarinova, clinical pharmacologist at the Center for Predictive Medicine and Bioinformatics, Republican Clinical Hospital No. 3. Address: 677027, Yakutsk, 34 Kirova Str.
Nadezhda E. Maksimova, biologist at the Center for Predictive Medicine and Bioinformatics, Republican Clinical Hospital No. 3. Address: 677027, Yakutsk, 34 Kirova Str.
Egor S. Prokopiev, director of E.N. Andreev Phthisiology Research and Practice Center. Address: 677015, Yakutsk, 93 Petra Alekseeva Str. E-mail: ftiziatria-2010@mail.ru
Alexander F. Kravchenko, Dr. med. habil., deputy director for outpatient care of E.N. Andreev Phthisiology Research and Practice Center. Address: 677015, Yakutsk, 93 Petra Alekseeva Str. E-mail: kravchenkoaf@tub.ykt.ru.
ORCID: https://orcid.org/0000-0002-9210-3407
Olga V. Tatarinova, Dr. med. habil., chief physician of Republican Clinical Hospital No. 3. Address: 677027, Yakutsk, 34 Kirova Str. E-mail: guzrb3@yandex.ru. ORCID: https://orcid.org/0000-0001-7717-9174
Alexander I. Vengerovsky, Dr. med. habil., professor, head of the Department of pharmacology, Siberian State Medical University of the Ministry of Healthcare. Address: 634034, Tomsk, 39 Uchebnaya Str. E-mail: pharm-sibgmu@rambler.ru. ORCID: https://orcid.org/0000-0001-5094-3742
Dmitry A. Sychev, Dr. med. habil., professor, academician of RAS, rector of Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare. Address: 125445, Moscow, 38 Smol`naya Str. E-mail: rmapo@rmapo.ru.
ORCID: https://orcid.org/0000-0002-4496-3680
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