Pharmacokinetic assessment of isoniazid and acetylisoniazid in carbon tetrachloride-induced liver injury model in wistar rats
- Vol.15(3), Jul-Sep
- Mumbai Wolter Kluwer 2023
- 139-145p.
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 (CCl 4 ) and preclinical drug-induced liver injury (DILI) model induced with CCl 4 + 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 CCl 4 intraperitoneal injection on day 0 to induce an animal model of DILI. Group I rats received CCl 4 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 CCl 4 -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 CCl 4 + 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 CCl 4 + Isoniazid+Rifampicin+Pyrazinamide (HRZ) group compared with the CCl 4 + H group ( P < 0.05). Biochemical, histological, and antioxidant changes were consistent with the new liver injury model’s development.