OBJECTIVES: The aim of the study was to predict human intestinal permeability and the fraction absorbed of an oral dose of a promising trioxane anti-malarial drug (CDRI 99/411) using the single-pass intestinal perfusion technique (SPIP) in rats. METHODS: Effective permeability coefficients (P eff) in anaesthetized rats were determined for marker compounds and the trioxane derivative 99/411. Drug solution in perfusion buffer was perfused through intestine with a flow rate of 0.2 ml/min and samples were taken from an outlet tubing at different time points up to 120 min. Drug concentrations in samples were determined using RP-HPLC. KEY FINDINGS: The effective permeability coefficient values of marker compounds obtained in rats were compared with published data for human intestinal permeability (P eff (human)) and human fraction absorbed (F(a) (human)) to establish an in-house model. Strong correlations were found between rat and human values for markers (P eff (human) = 1.039 P eff (rat) - 0.1815; R2 = 0.970 and F(a) (human) = 0.15621n (P eff (rat) + 0.7232; R2 = 0.927). Subsequently the human permeability and fraction dose absorbed in human were predicted for 99/411 using the obtained rat permeability value and established correlations. P eff in human predicted from the model was found to be 7.05 x 10(-4) cm/s and F(a) value in human was predicted around 1. CONCLUSIONS: Considering the high correlation of rat Peff values with those of human reported values, it can be concluded that the developed in-house model is reliable and can be used preliminarily, to predict human permeability and fraction dose absorbed of any test compound. From predicted results, 99/411 was found to have high permeability and possibly complete absorption in human.
OBJECTIVES: The aim of the study was to predict human intestinal permeability and the fraction absorbed of an oral dose of a promising trioxane anti-malarial drug (CDRI 99/411) using the single-pass intestinal perfusion technique (SPIP) in rats. METHODS: Effective permeability coefficients (P eff) in anaesthetized rats were determined for marker compounds and the trioxane derivative 99/411. Drug solution in perfusion buffer was perfused through intestine with a flow rate of 0.2 ml/min and samples were taken from an outlet tubing at different time points up to 120 min. Drug concentrations in samples were determined using RP-HPLC. KEY FINDINGS: The effective permeability coefficient values of marker compounds obtained in rats were compared with published data for human intestinal permeability (P eff (human)) and human fraction absorbed (F(a) (human)) to establish an in-house model. Strong correlations were found between rat and human values for markers (P eff (human) = 1.039 P eff (rat) - 0.1815; R2 = 0.970 and F(a) (human) = 0.15621n (P eff (rat) + 0.7232; R2 = 0.927). Subsequently the human permeability and fraction dose absorbed in human were predicted for 99/411 using the obtained rat permeability value and established correlations. P eff in human predicted from the model was found to be 7.05 x 10(-4) cm/s and F(a) value in human was predicted around 1. CONCLUSIONS: Considering the high correlation of rat Peff values with those of human reported values, it can be concluded that the developed in-house model is reliable and can be used preliminarily, to predict human permeability and fraction dose absorbed of any test compound. From predicted results, 99/411 was found to have high permeability and possibly complete absorption in human.