Pharmacokinetic evaluation of poorly soluble compounds formulated as nano- or microcrystals after intraperitoneal injection to mice

Intraperitonial (i.p.) delivery during initial stages of drug discovery can allow efficacy readouts for compounds which have suboptimal pharmacokinetics (PK) due to poor physiochemical properties and/or oral bioavail-ability. A major limitation for widespread use of i.p. administration is the paucity of published data and unclear mechanisms of absorption, particularly when using complex formulations. The aim of the present study was to investigate the PK of poorly soluble compounds with low oral bioavailability when administered i.p. as crys-talline nano-and microsuspensions. Three compounds, with varying aqueous solubility (2, 7, and 38 mu M, at 37 degrees C), were dosed to mice at 10 and 50 mg/kg. In vitro dissolution confirmed that nanocrystals dissolved faster than microcrystals and hence were expected to result in higher exposure after i.p. dosing. Surprisingly, the increase in dissolution rate with decrease in particle size did not result in higher in vivo exposure. In contrast, the micro-crystals showed higher exposure. The potential of smaller particles to promote access to the lymphatic system is hypothesized and discussed as one plausible explanation. The present work demonstrates the importance of understanding physicochemical properties of drug formulations in the context of the microphysiology at the delivery site and how that knowledge can be leveraged to alter systemic PK.

Automated summary

Intraperitoneal (i.p.) delivery of poorly soluble compounds with low oral bioavailability can provide efficacy readouts during initial stages of drug discovery. However, the mechanisms of absorption in complex formulations are unclear, limiting the widespread use of i.p. administration. This study investigated the pharmacokinetics of crystalline nano- and microsuspensions administered i.p. and found that smaller particles did not result in higher in vivo exposure, suggesting a potential role of the lymphatic system in absorption.