Absorption/permeability predictor

From an analysis ofthe key properties of compounds in the World Drug Index (WDI), the now well-accepted rule-of-5 has been derived [136, 137]. It was concluded that compounds are most likely to have poor absorption when the molecular weight is more than 500, the calculated octanol/water partition coefficient (Clog P) is more than 5, number of H -bond donors is more than 5, and the number of H-bond acceptors is more than 10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The rule-of-5 should be seen as a qualitative absorption/permeability predictor [138], rather than a quantitative predictor [139]. The rule-of-5 is not predictive for bioavailability as sometimes mistakenly assumed. An important factor for bioavailability in addition to absorption is liver first-pass effect (metabolism). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [140,141]. 

Figure 17.1 Correlation of rank order for ADMET Risk and human intestinal absorption (H IA%). The ADMET Risk score ranged from 0 to 5, with 5 being compounds with the greatest risk of having poor ADMET properties. Within a single ADMET Risk number, the compounds were ranked according to ascending estimated human jejunal permeability (ADMET Predictor, Simulations Plus, Inc.). Spearman rank correlation coefficient was 0.7 (pcO.OOl).

Many organizations use colon adenocarcinoma (Caco-2) for detailed study of permeability however, this method can be resource intensive. Parallel artificial-membrane permeability (PAMPA) [19] has proven to be a reliable predictor of passive transcellular permeability for intestinal absorption prediction. It is also useful to interpret results of cell-based discovery assays, in which cell-membrane permeability is limiting. Finally, pTf provides insight into the pH dependence of solubility and permeability. It can be measured [20] or calculated to get an understanding of the regions of the intestine in which the compound will be best absorbed, as well as to anticipate the effect of pH on solubility and pemieability. Permeability at the blood-brain barrier (BBB) also can be rapidly profiled [21]. 

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