Solubility permeability screens

E. Poor ADME properties - B. Aqueous solubility and blunt PERMEABILITY SCREENS... 

To conclude, it is not unusual that FA data for the same compound varies with 50% in the literature, for example, FA can be reported as either 10 or 60%, generally sorted as poor and intermediate FA, respectively. If such data is used for training the in silico model, the model will to a large extent be based on noise leading to poor external predictions and noninterpretable results. In our mind, it is more relevant to estimate the FA on the basis of in silico solubility and permeability screens. 

The reader quickly realizes whether poor solubility might be a confounding factor for permeability screening of a combinatorial library. In my experience, the existing batchmode solubility calculation progranunes generate similar... 

Poor aqueous solubility, a compound related factor rather than an assay related factor, has a major effect by introducing noise into permeability screening and hence has an effect on making computational model building very difficult. It must be stressed that the compound solubility factor virtually never appears as an explicit consideration in the published permeability literature. Compound sets are published that are used to validate in vitro cell based absorption assays. Validation usually means obtaining an acceptable correlation between human fraction absorbed data and in vitro permeability data. The absorption data always include the experimentally very well controlled but compound number limited human fraction absorbed data that are used to define absorption ranges in the FDA bioavailability waiver guidelines. This limited compound set is then supplemented with additional compounds chosen from published human absorption literature. In our own work we have been able to accumulate... 

Figure 16.2 sets the stage for the types of solubility among currently synthesized compounds that are likely to be submitted to a permeability screen like a Caco-2 assay. In this type of assay a variety of biological transporters are present that mediate both absorption and efflux. The movement of a compound through the Caco-2 polarized cell layer through the action of... 

The lengthy permeability chapter (Chapter 7) recounts the study of many different artificial membrane formulations, comparing transport results of each to human jejunal permeabilities. A very promising in vitro screening system was described the double-sink sum-Pe PAMPA GIT model. It is most applicable to molecules that are classified as soluble in the BCS scheme. 

Several attempts have been made to estimate the dose required in humans in relation to a drug s potency, and to put this into the context of solubility and permeability for an optimal oral drug [2, 3]. A relatively simple example of this is where a 1.0 mg kg-1 dose is required in humans, then 52 pg mL"1 solubility is needed if the permeability is intermediate (20-80%) [3]. This solubility corresponds approximately to 100 pM of a compound with a MW of 400 g mol-1. Most screening activities for permeability determinations in, e.g., Caco-2, are made at a concentration of 10 pM or lower due to solubility restrictions. The first implication of this is that the required potency for these compounds needs to correspond to a dose of <0.1 mg kg-1 in humans if the drug should be considered orally active. Another implication would be the influence of carrier-mediated transport (uptake or efflux), which is more evident at low concentrations. This could result in low permeability coefficients for compounds interacting with efflux transporters at the intestinal membrane and which could either be saturated or of no clinical relevance at higher concentrations or doses. 

Solvents used to increase solubility for compounds during screening of permeability across the cell monolayers, together with commonly used excipients for formulations, can also affect the barrier as they contain ingredients which enhance drug absorption [100, 151]. There are different mechanisms by which these compounds can modulate the barrier [4, 149, 150] for example, they may increase the tight junctional pathway inhibiting carrier-mediated transport, or cholesterol... 

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