Pharmacokinetic Assessment of Isoniazid and Acetylisoniazid in Carbon Tetrachloride-Induced Liver Injury Model in Wistar Rats

Swati Sharma; Aishwarya Anand; Nipun Verma; Vishal Sharma; Alka Bhatia; Amol N Patil; Dibyajyoti Banerjee

doi:10.4103/jpbs.jpbs_320_23

Pharmacokinetic Assessment of Isoniazid and Acetylisoniazid in Carbon Tetrachloride-Induced Liver Injury Model in Wistar Rats

J Pharm Bioallied Sci. 2023 Jul-Sep;15(3):139-145. doi: 10.4103/jpbs.jpbs_320_23. Epub 2023 Aug 15.

Authors

Swati Sharma¹, Aishwarya Anand², Nipun Verma³, Vishal Sharma⁴, Alka Bhatia¹, Amol N Patil², Dibyajyoti Banerjee¹

Affiliations

¹ Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
² Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
³ Department of Hepatology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
⁴ Department of Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Abstract

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.

Keywords: Acetylisoniazid; carbon tetrachloride; drug-induced liver injury; isoniazid; pharmacokinetics.