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%.

Objective: To develop and validate simple, sensitive, accurate and selective UPLC-MS/MS method for quantification of paromomycin (PARO) in mice plasma.Methods: Precipitation method was used for the extraction of plasma samples, an aliquot of 25 µl plasma samples was extracted using 10% perchloric acid in water. Chromatographic separation was performed using waters acquity ultra-performance liquid chromatography (UPLC) columns, BEH HILIC (50 mm× 2.1 mm, 1.7 µm) by a gradient mixture of acetonitrile and water (both containing 0.005% v/v trifluro acetic acid) as a mobile phase at the flow rate of 0.2 ml/min. The analyte was protonated in the positive electrospray ionization (ESI) interface and detected in multiple reactions monitoring (MRM) modes using the transition m/z 308.60-455.30.Results: The method had a short chromatographic run time of 3 min. Calibration curves were linear over wide ranges of 50.51-5019.22 ng/ml. The between and within-batch precision and accuracy of the method was determined by using 4 quality control samples, the highest % CV observed was 11.06. The mean recovery values are 78.17, 101.17 and 92.58 at low, medium and high-quality control levels; respectively.Conclusion: It was concluded that the developed and validated UPLC-MS/MS method was rapid, sensitive, accurate, precise, linear, and specific. Therefore, this method can be used for quantification of PARO in mice plasma with various advantages over the reported methods.

Pinjari, et al.: Different Formulation Approach for ParomomycinParomomycin, an aminoglycoside antibiotic, is used to treat visceral leishmaniasis as an intramuscular injection daily for 21 days since it has limited oral bioavailability. The objective of this investigation is to improve the oral bioavailability through formulation development for increased patient compliance and convenience. Comparative pharmacokinetic studies of intravenous and oral administration of paromomycin in mice to evaluate different formulation approaches to increase oral bioavailability were carried out. Following intravenous injection of 15 mg/kg to mice, paromomycin exhibited low plasma clearance (8 ml/min/kg) with elimination half-life of 2.6 h. Following oral administration of 500 mg/kg of a suspension formulation using carboxymethylcellulose to mice, referred to as formulation 1, paromomycin showed very low or negligible oral bioavailability (%F=0.3). Different formulation approaches were made by employing a variety of FDA-approved novel excipients belonging to glycols, fatty acids, alcohols and surfactants alone and in various combinations. In vivo pharmacokinetic studies with these formulations demonstrated improved oral bioavailability of paromomycin in mice. Formulation approaches tested in the present research project were successful in improving the oral bioavailability of paromomycin from 0.3% to a maximum of 9%. Overall, the increase in paromomycin bioavailability ranged 1-30 fold with different formulations compared to carboxymethylcellulose formulation. Formulation with 10% Gelucire 44/14, 10% Solutol HS 15, 30% propylene glycol and 50% normal saline showed higher bioavailability compared to formulation 1. This research provided evidence that improved bioavailability of paromomycin can be achieved through formulation development, which eventually could result in making the most tedious and painful intramuscular therapy redundant.