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Purpose: Our main aim is to determine the effective intestinal permeability (P eff) in the rat jejunum in situ for 10 compounds with different absorption mechanisms and a broad range of physico chemical properties, and then compare them with corresponding historical human in vivo P eff values.

Methods: The rat P eff coefficients are determined using an in situ perfusion model in anaesthetized animals. The perfusion flow 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 physiological function of the rat intestine during perfusions.

Results: The P eff for passively absorbed compounds is on average 3.6 times higher in humans compared to rats (P eff,man = 3.6 [middle dot] P eff,rat 0.03[middle dot]10-4; R^2 = 1.00). Solutes with carrier-mediated absorption deviate from this relationship, which indicates that an absolute scaling of active processes from animal to man is difficult, and therefore needs further investigation. The fraction absorbed of drugs after oral administration in humans (fa) can be estimated from 1 - e-(2[middle dot]Peff,man[middle dot]tres /r[middle dot]2.8).

Conclusions: Rat and human jejunum P eff estimates of passively absorbed solutes correlate highly, and both can be used with precision to predict in vivo oral absorption in man. The carrier-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.

(C)1996 Kluwer Academic Publishers