BACKGROUND: Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB (tuberculosis) and autoimmune granulomatous liver diseases. Antitubercular (ATT) and other drugs' metabolism in the presence of a specific type of liver injury is not well understood. The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG (Bacillus Calmette-Guérin) vaccine, further studying it in the presence of ATT dosing, and analyze the pharmacokinetics of isoniazid, rifampicin, and their respective primary metabolites. METHODS: We used 56 rats in seven equal groups. Group I functioned as a normal control (NC) receiving normal saline only. Groups II-IV received intravenous injections of low-, medium-, and high-dose BCG vaccine daily for 21 days. Groups V, VI, and VII received isoniazid (H) alone, rifampicin (R) alone, and isoniazid + rifampicin(HR) for a subsequent 15 days in addition to high dose BCG for the first 21 days, respectively. Liver function tests (LFT) were monitored on days 0, 21, 28, and 36. Rats were sacrificed later for oxidative stress and histopathological examination. RESULTS: The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21 (p <
0.05). Isoniazid, rifampicin, and combination intervention groups demonstrated normalization of the BCG-led LFT changes. Histology and oxidative stress parameters confirmed model development and biochemical changes. Isoniazid area under the curve (AUC) showed a reduction of 16.9% in BCG + HR group in comparison to the BCG + H group (p = 0.01). Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG + HR group in comparison to the BCG + R group (p = 0.001). CONCLUSION: A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.