Carbamate Prodrugs Restrict Metabolism and Improve the Pharmacokinetics of Isoniazid.

Isoniazid (INH), an important first-line drug in tuberculosis (TB) treatment, faces significant challenges primarily due to hepatotoxicity and peripheral neuropathy as major side effects. These adverse effects often lead to poor patient compliance and treatment dropouts. The INH's metabolism is responsible for these adverse effects. INH's reactive terminal -NH group is involved in its undesired metabolic transformations. To address this, we designed and synthesized carbamate-based prodrugs of INH by masking the -NH group to reduce its metabolic activity. Herein, we report our efforts to develop such prodrugs and their impact on metabolism and the pharmacokinetic profile of free INH. The stability, bioconversion, and pharmacokinetic profile with detailed metabolite analysis of these prodrugs were determined in mice. The lead prodrug demonstrated enhanced systemic exposure of free INH (1.5-fold, AUC ≈ 3948 ng·h/mL), reduced formation of undesired metabolites, and prolonged half-life (1.3-fold, ≈ 0.88 h) compared to naive INH. This prodrug approach represents a promising strategy for safer and more effective TB therapy, with the potential for less frequent dosing and improved patient compliance.