DEPENDENCE OF PHARMACOKINETICS AND HEPATOTOXIC ACTION OF ISONIAZID ON ITS ACETYLATION RATE IN PATIENTS WITH DRUG-SENSITIVE PULMONARY TUBERCULOSIS


Дәйексөз келтіру

Толық мәтін

Ашық рұқсат Ашық рұқсат
Рұқсат жабық Рұқсат берілді
Рұқсат жабық Рұқсат ақылы немесе тек жазылушылар үшін

Аннотация

Liver injury is a dangerous adverse drug reaction (ADR) that can develop in response to isoniazid. In patients with tuberculosis (TB), individual responsiveness to isoniazid has been associated with the presence in genome of allelic variants of N-acetyltransferase 2 (NAT2) gene. 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 42 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% d: 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.

Толық мәтін

Рұқсат жабық

Авторлар туралы

Natalia Krasnova

M.K. Ammosov North-Eastern Federal University

Email: krasnova14@mail.ru
PhD in Medicine, associate professor of the Department «Hospital Therapy, Occupational Diseases and Clinical Pharmacology», Medical Institute 677013, Yakutsk, 27 Oyunskogo Str

Vyacheslav Nikolaev

Yakutsk Scientific Center for Complex Medical Problems

Email: nikolaev1126@mail.ru
PhD in Biology, senior researcher at the Department of epidemiology of chronic noncommunicable diseases 677019, Yakutsk, 4 Sergelyakhskoe Highway

Efrosinya Efremova

E.N. Andreev Phthisiology Research and Practice Center

Email: efremovaen@tub.ykt.ru
phthisiatrician at the Department of patients with tuberculosis of the respiratory organs 677015, Yakutsk, 93 Petra Alekseeva Str

Alexandra Egorova

E.N. Andreev Phthisiology Research and Practice Center

Email: egorovaaa@tub.ykt.ru
phthisiatrician at the Department of patients with tuberculosis of the respiratory organs

Tatyana Tatarinova

Republican Clinical Hospital No. 3

clinical pharmacologist at the Center for Predictive Medicine and Bioinformatics 677027, Yakutsk, 34 Kirova Str

Nadezhda Maksimova

Republican Clinical Hospital No. 3

biologist at the Center for Predictive Medicine and Bioinformatics 677027, Yakutsk, 34 Kirova Str

Egor Prokopiev

E.N. Andreev Phthisiology Research and Practice Center

Email: ftiziatria-2010@mail.ru
director 677015, Yakutsk, 93 Petra Alekseeva Str

Alexander Kravchenko

E.N. Andreev Phthisiology Research and Practice Center

Email: kravchenkoaf@tub.ykt.ru
Dr. med. habil 677015, Yakutsk, 93 Petra Alekseeva Str

Olga Tatarinova

Republican Clinical Hospital No. 3

Email: guzrb3@yandex.ru
Dr. med. habil., chief physician 677027, Yakutsk, 34 Kirova Str

Alexander Vengerovsky

Siberian State Medical University of the Ministry of Healthcare

Email: pharm-sibgmu@rambler.ru
Dr. med. habil., professor, head of the Department of pharmacology 634034, Tomsk, 39 Uchebnaya Str

Dmitry Sychev

Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare

Email: rmapo@rmapo.ru
Dr. med. habil., professor, academician of RAS, rector 125445, Moscow, 38 Smol'naya Str

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