Oral bioavailability and in situ absorption of etoposide in rat

Abstract

Etoposide, an anticancer drug, has low oral bioavailability in humans which is due to low equilibrium aqueous solubility, slow dissolution rate, and instability at pH 1.3. Etoposide coprecipitate with PEG 8000 in a ratio of 1:10 (PEG weight fraction of 0.91) increased the solubility 2-fold and dissolution rate 42-fold. The oral bioavailability study of etoposide formulations was conducted in male Sprague-Dawley rats using a balanced crossover design. The absolute oral bioavailability of etoposide from coprecipitate, solution and powder was 5.56 ± 2.32, 10.16 ± 7.11 and l.29 ± 0.62%, respectively. No significant difference in oral bioavailability between solution and coprecipitate formulation was found but both were significantly higher than that of etoposide powder. The variability in serum concentrations and oral bioavailability of etoposide from coprecipitate formulation was much smaller than that from solution formulation. The very low extent of etoposide absorption even from a solution formulation (10.16%), in contrast to that in humans, suggested that factors other than the physicochemical properties may be responsible for the poor oral absorption of etoposide in rat. The in situ absorption studies in rats demonstrated very poor absorption of etoposide from stomach and the whole intestine by both Doluisio and Levine techniques. Bile salt (sodium taurocholate at 10 mM) reduced etoposide absorption. Thus, results from the in situ and in vivo absorption studies suggested that etoposide absorption is permeation rate limiting in rat. Therefore, rat may not be a good animal model for studying etoposide absorption from oral formulations with improved dissolution rate of etoposide.