RESUMO
OBJECTIVE: The objective of this study is to investigate in vitro Caco2 permeability, metabolism and in vivo pharmacokinetic (PK) properties of paromomycin to develop an efficient dosage form with improved oral bioavailability. MATERIALS AND METHODS: For the purpose, Caco2 permeability assay, mouse microsomal stability assay and in vivo PKs in male BALB/c mice were performed. RESULTS: In Caco-2 permeability assay, paromomycin showed negligible permeability in the apical to basolateral (A-to-B) direction and vice versa (B-to-A). Marginal increase in permeability with the use of P-glycoprotein (P-gp) inhibitor, namely, verapamil suggesting paromomycin could be a P-gp substrate. Paromomycin was unstable in liver microsomes of mouse. Paromomycin showed good PK properties after intravenous dose in male BALB/c mice which included low plasma clearance, i.e., <10% of hepatic blood flow in mice, high volume of distribution (Vd), and half-life (T½) of 2.6 h. Following per oral dose, it exhibits low oral bioavailability (0.3%) with carboxymethyl cellulose formulation. Oral plasma exposure increased in mice by 10% and 15% after pretreatment with P-gp inhibitor verapamil and CYP inhibitor 1-Aminobenztriazole, respectively. CONCLUSION: Comparatively significant increase in oral plasma exposure of paromomycin was observed with an alternative oral formulation approach, use of P-gp and CYP inhibitors resulting in improved oral bioavailability up to 16%.
