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Background: N-acetyl transferase 2 (NAT2) polymorphism testing could not see the light of success as a biomarker tool in tuberculosis management. Additionally, the antitubercular treatment (ATT) drug's reintroduction regimen variations exist because of the scarcity of robust preclinical evidence on ATT drug metabolism. Objective: The experiment was planned to understand the pharmacokinetic (PK) behavior of isoniazid and acetylisoniazid (AcINH) in a Wistar rat model of acute liver injury induced by carbon tetrachloride (CCl4) and preclinical drug-induced liver injury (DILI) model induced with CCl4 + anti-Tuberculosis (TB) drugs together. Materials and Methods: Thirty rats were used for the experiment and were divided into five groups. All rats were administered a single 0.5 ml/kg CCl4 intraperitoneal injection on day 0 to induce an animal model of DILI. Group I rats received CCl4 alone. Groups II--V were started on additional gavage feedings of isoniazid (H) alone, H plus rifampicin (R), H plus pyrazinamide (Z), and H, R, and Z together, respectively, daily for 21 days subsequently. Isoniazid and AcINH PK assessment was accomplished on day 20 of continuous once-daily dosing. Liver function test (LFT) monitoring was done at baseline on days 1, 7, and 21. On the last day of experiments, all experimental rats were sacrificed. Results: Three-week ATT administration sustained the CCl4-induced LFT changes. Area under the curve (AUC) values for isoniazid and AcINH were found to be 2.24 and 1.69 times higher in the H + R group compared with the CCl4 + H group, respectively (P < 0.05). Isoniazid and AcINH maximum concentration (Cmax) reached the highest, while isoniazid clearance reached the lowest in the H + R group. AcINH AUC increased by double in the CCl4 + Isoniazid+Rifampicin +Pyrazinamide (HRZ) group compared with the CCl4 + H group (P < 0.05). Biochemical, histological, and antioxidant changes were consistent with the new liver injury model's development. Conclusion: Rifampicin almost doubles up the isoniazid and AcINH exposure, in presence if DILI. [ABSTRACT FROM AUTHOR]

Background: We investigated the pharmacokinetic behavior of pyrazinamide (PZA) and pyrazinoic acid (PA) in the presence of carbon-tetrachloride (CCl4) plus antitubercular treatment (ATT) drug-induced liver injury (DILI) in rats. Methods: Thirty rats utilized in the experiment were separated equally into five groups. Each rat was injected with 0.5 ml/kg CCl4 intra-peritoneal injection on day zero. Group, I rats did receive only CCl4 (single i.p. injection, 0.5 ml/Kg in olive oil in a 1:1 ratio). Groups II, III, IV, and V did receive daily oral PZA, PZA plus isoniazid (INH), rifampicin (RMP) plus pyrazinamide (PZA), and three drugs together, respectively, for 21-days. Pharmacokinetic sampling was performed at 0, 0.5,1,3,6,12 and 24 hours post-dosing on day-20. Liver function test (LFT) was assessed at days 0,1,7, and 21 days after CCl4 and ATT administration, and rats were sacrificed on the last experiment day. Results: ATT treatment maintained the liver function changes initiated by CCl4 administration. An evidential LFT rise was observed in groups administered with pyrazinamide. Co-administration of Isoniazid caused a 2.02 and 1.78 times increase in Area-under-the-curve (AUC) values of PZA and PA, respectively (p < 0.05). Histological and oxidative-stress changes supported the biochemical and pharmacokinetic observations. Conclusion: The enzyme inhibitory capacity of isoniazid is well-preservd in CCl4-induced liver injury. [ABSTRACT FROM AUTHOR]

Background: Several phyto-chemicals have been identified and suggested as potential therapeutic options for hepatotoxicity management. Objective: To assess the hepatoprotective effect of scopoletin, a pure phyto-chemical, in carbon tetrachloride (CCl4)-induced hepatotoxicity model in Wistar rats. Methods: Thirty-six rats in total, six in each group, were utilized in this study. Animals in group 1 received normal saline; those in group 2 received carbon tetrachloride in olive oil (0.5 ml/kg, i.p. in ratio 1:1); those in groups 3, 4, and 5 received oral scopoletin (1 mg/kg, 5 mg/kg, 10 mg/kg dose-wise groups); and those in group 6 received N-acetyl cysteine (NAC) 150 mg/kg. Blood sampling was performed on day - 3, day 1, and day 7 of the CCl4 administration. Rats were sacrificed on day 7 of the experiment for histological examination and oxidative stress measurement of the liver. Results: The 5 mg/kg scopoletin group showed a maximum reduction in AST levels [727.33 ± 29.15 in medium dose (MD) group vs 1526.66 ± 60.72 in the experimental control (EC) group (P < 0.001) and ALT levels of 532.66 ± 24.23 in MD group vs 894.83 ± 52.47 in EC (P < 0.01)]. The dose-dependent action was not observed with scopoletin doses. The protective effect of scopoletin was confirmed by MDA and GSH levels (P < 0.05) coupled with histo-pathological findings. In the present study, a reversible model of CCl4-induced hepatotoxicity was observed to get normalized in a week's time. Conclusion: The study confirms the hepatoprotective action of scopoletin in an acute model of hepatic injury with the putative anti-oxidant mechanism. [ABSTRACT FROM AUTHOR]