Carbamate Prodrugs Restrict In Vivo 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 in vivo metabolism is responsible for these adverse effects. INH’s reactive terminal −NH₂ group is involved in its undesired in vivo metabolic transformations. To address this, we designed and synthesized carbamate-based prodrugs of INH by masking the −NH₂ group to reduce its metabolic activity. Herein, we report our efforts to develop such prodrugs and their impact on in vivo metabolism and the pharmacokinetic profile of free INH. The ex vivo stability, bioconversion, and in vivo pharmacokinetic profile with detailed metabolite analysis of these prodrugs were determined in mice. The lead prodrug 1d 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, t_1/2 ≈ 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.

Carbamate prodrugs of INH were designed and synthesized to mask its reactive -NH₂ group, resulting in reduced metabolism and improved PK profile. Lead 1d showed 1.5x AUC, prolonged t₁/₂, and potential for safer TB therapy.