METABOLIC PROFILE INVESTIGATION REVEALS WIDE VARIABILITY IN THE EXPOSURE OF ISONIAZID AND ITS HEPATOTOXIC METABOLITES IN TUBERCULOSIS PATIENTS

초록

Background Isoniazid (INH) is a first‐line agent for the treatment of tuberculosis (TB), a global health crisis. INH and its metabolites exposure variability could influence the effectiveness and toxicity of INH‐based therapy. To assess the interindividual differences in INH metabolism and distribution we investigated the impact of clinical and pharmacogenetic factors on the metabolic profiles of the drug. Methods A targeted profiling of INH and its four major metabolites (i.e., acetylisoniazid, isonicotinic acid, hydrazine, and acetylhydrazine) in plasma of 965 TB patient was performed using liquid chromatography–tandem mass spectrometry. N‐acetyltransferase 2 (NAT2) genotypes were also determined for patients’ acetylator phenotypes. After removing non‐compliance subjects, 876 TB patients’ INH metabolic profiles, including 345 rapid, 412 intermediate and 119 slow acetylator, were selected for subsequent analyses. The distribution of INH and its metabolites was examined during 24 hour time‐course to characterize their exposure variabilities in different acetylators and clinical factors. Results The median concentration of INH in its time‐course was 2.5‐ fold and 1.8‐ fold higher in slow acetylator compared to rapid and intermediate acetylator, respectively. Median concentrations of hydrazine, the hepatotoxic metabolite, were over 1.7‐ fold higher in slow acetylator compared to other NAT2 phenotypes. The meta-bolic ratio distribution of INH was significantly associated with NAT2 phenotypes. Conclusion INH metabolic profiles are markedly associated with acetyl-ator phenotypes of TB patients. Our findings provide a proof of concept towards implementing an acetylator phenotype‐based dosing for a safe and effective INH‐ based therapy.