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.
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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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