Drug absorption models limitations

Camenisch, G., Van de Waterbeemd, H Folkers, G. Review of theoretical passive drug absorption models historical background, recent development and limitations. Pharm. Acta. Helv. 1996, 73, 309-327. 

A wide array of drug absorption models and powerful computational facilities are available to population and traditional PK modelers, yet adequate absorption models are seldom available, presented in the literature, or estimated during drug development. The factor limiting the development of adequate absorption models is... 

The advantages of the in situ techniques include an intact blood supply multiple samples may be taken, thus enabling kinetic studies to be performed. A fundamental point regarding the in situ intestinal perfusion method is that the rat model has been demonstrated to correlate with in vivo human data [46 19], Amidon et al. [36] have demonstrated that it can be used to predict absorption for both passive and carrier-mediated substrates. However, the intestinal luminal concentrations used in rat experiments should reflect adequately scaled and clinically relevant concentrations to ensure appropriate permeability determinations [50], There are limitations of the in situ rat perfusion models. The assumption involved in derivation of these models that all drug passes into portal vein, that is drug disappearance reflects drug absorption, may not be valid in some circumstances as discussed below. 

Limitations of Ex Vivo and in Situ Models for Drug Absorption and Metabolism Studies... 

Absorption rate coefficients and permeability values obtained through different systems, i.e. in vitro or in situ, finally are determined with the objective in mind of predicting the fraction of a dose that will be absorbed through the intestine when the drug is orally administered. In order to use the data obtained in those systems it is essential to validate them properly. The present section reviews the capability of the parameters representatives of the absorption determining with different techniques to predict in vivo drug absorption in absence of any limited step (as dissolution or solubility) by means of the previously described model and Eq. (16). In particular, the absorption rate constant obtained with an in situ close loop assay, permeability through Caco-2 cell lines, and PAM PA models have been examined. 

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