Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships

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dc.contributor.authorUlanova, Viktorija
dc.contributor.authorKivrane, Agnija
dc.contributor.authorViksna, Anda
dc.contributor.authorPahirko, Leonora
dc.contributor.authorFreimane, Lauma
dc.contributor.authorSadovska, Darja
dc.contributor.authorOzere, Iveta
dc.contributor.authorCirule, Andra
dc.contributor.authorSevostjanovs, Eduards
dc.contributor.authorGrinberga, Solveiga
dc.contributor.authorBandere, Dace
dc.contributor.authorRanka, Renate
dc.contributor.institutionResearch Professor (Tenured Professor) Group at the Faculty of Pharmacy
dc.contributor.institutionDepartment of Pharmaceutical Chemistry
dc.date.accessioned2024-05-02T11:10:01Z
dc.date.available2024-05-02T11:10:01Z
dc.date.issued2024-03
dc.descriptionPublisher Copyright: Copyright © 2024 Ulanova, Kivrane, Viksna, Pahirko, Freimane, Sadovska, Ozere, Cirule, Sevostjanovs, Grinberga, Bandere and Ranka.
dc.description.abstractObjectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes.  Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia ( N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0 h), 2 h and 6 h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student's t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC.  Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotype-dependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity. Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies.en
dc.description.statusPeer reviewed
dc.format.extent20
dc.format.extent2192217
dc.identifier.citationUlanova, V, Kivrane, A, Viksna, A, Pahirko, L, Freimane, L, Sadovska, D, Ozere, I, Cirule, A, Sevostjanovs, E, Grinberga, S, Bandere, D & Ranka, R 2024, 'Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships', Frontiers in Pharmacology, vol. 15, 1332752. https://doi.org/10.3389/fphar.2024.1332752
dc.identifier.doi10.3389/fphar.2024.1332752
dc.identifier.issn1663-9812
dc.identifier.otherPubMedCentral: PMC10995391
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/15462
dc.identifier.urlhttps://www-webofscience-com.db.rsu.lv/wos/alldb/full-record/WOS:001197103600001
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85189647869&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofFrontiers in Pharmacology
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectGSTM1
dc.subjectisoniazid
dc.subjectpharmacogenomics
dc.subjectNAT2
dc.subjecttuberculosis
dc.subjectCYP2E1
dc.subject3.1 Basic medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectPharmacology (medical)
dc.subjectPharmacology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleEffect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationshipsen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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