COMPARISON BETWEEN PERMEABILITY COEFFICIENTS IN RAT AND HUMAN JEJUNUM

Purpose. Our main aim is to determine the effective intestinal permeab ility (P-eff) in the rat jejunum in situ for 10 compounds with differe nt absorption mechanisms and a broad range of physico chemical propert ies, and then compare them with corresponding historical human in vivo P-eff values. Methods. The rat P-eff coefficients are determined usin g an in situ perfusion model in anaesthetized animals. The perfusion f low rate used is 0.2 ml/min, which is 10 times lower than that used in humans. The viability of the method is assessed by testing the physio logical function of the mt intestine during perfusions. Results. The P -eff for passively absorbed compounds is on average 3.6 times higher i n humans compared to rats (P-eff,P-man = 3.6 . P-eff,P-rat + 0.03 . 10 (-4); R(boolean AND)2 = 1.00). Solutes with carrier-mediated absorptio n deviate from this relationship, which indicates that an absolute sca ling of active processes from animal to man is difficult, and therefor e needs further investigation. The fraction absorbed of drugs after or al administration in humans (fa) can be estimated from 1 - e(-(2 . Pef f,man . tres/r . 2.8)). Conclusions, Rat and human jejunum P-eff-estim ates of passively absorbed solutes correlate highly, and both can be u sed with precision to predict in vivo oral absorption in man. The carr ier-mediated transport requires scaling between the models, since the transport maximum and/or substrate specificity might differ. Finally, we emphasize the absolute necessity of including marker compounds for continuous monitoring of intestinal viability.