Passive permeability

Liposomes, which are lipid bilayer vesicles prepared from mixtures of lipids, also provide a useful tool for studying passive permeability of molecules through lipid. This system has, for example, been used to demonstrate the passive nature of the absorption mechanism of monocarboxylic acids [131]. Liposome partitioning of... 

Artursson P, Neuhoff S, Matsson P, Tavelin S (2006) Passive permeability and active transport models for the prediction of oral absorption. In Taylor JB, Triggle DJ (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, Sect 5.11... 

There are several approaches to estimating absorption using in vitro methods, notably Caco-2 and MDCK cell-based methods or using methods that assess passive permeability, for example the parallel artificial membrane permeation assay (PAMPA) method. These are reviewed elsewhere in this book. The assays are very useful, and usually have an important role in the screening cascades for drug discovery projects. However, as discussed below, the cell-based assays are not without their drawbacks, and it is often appropriate to use ex vivo and/or in vivo absorption assays. 

Oral availability is a complex parameter that involves several chemical and physiological processes such as solubility, chemical stability, permeability and first-pass metabolism, to mention a few. All of these subprocesses depend on two different types of factor (i) interaction of the drug compound with certain macromolecules, such as the metabolism mediated by the cytochromes P450 family and (ii) interaction of the drug molecule with a certain chemical or biological environment, that will determine the solubility or the passive permeability. 

J. E., Influence of passive permeability on apparent P-glycoprotein kinetics, Pharm. Res. 2000, 37, 1456-1460. 

MDRl-directional transport ratio (B/A)/(A/B). b Passive permeability flO cm/s). 

In a study of p-glycoprotein substrates vs. non-substrates, Varma et al. [48] concluded that substrate molecules with high passive permeability overwhelmed the transporter while substrate molecules with moderate passive permeability were more affected by p-glycoprotein. Approximately half of 63 p-glycoprotein substrates studied had MW >400 and PSA > 75 indicating that larger, more polar molecules are more likely to be p-glycoprotein substrates. 

Mercury can influence ion, water, and nonelectrolyte transport in different cells [ 14, 77]. The cell membrane is believed to be the first point of attack by heavy metals however, intracellular enzymes and metabolic processes may also be inhibited [70, 78, 79]. The attachment of heavy metals to ligands in or on the plasma membrane may result in changes in passive permeability or selective blockage of specific transport processes. Many membrane transport systems are known to be sensitive to sulphydryl-group modification [ 14, 80, 81]. 

Varma, M.V.S., Sateesh, K. and Panchagnula, R. (2005) Functional role of P-glycoprotein in limiting intestinal absorption of drugs contribution of passive permeability to P-glycoprotein meditated efflux transport Molecular Pharmaceutics, 2, 12—21. 

In summary, most research groups focus on developing classification models to discriminate low-permeability compounds from medium- to high-permeability ones. The accuracy of correct grouping is ranged from 70% to 90% given the molecules in the data sets undergo the passive permeability mechanism. 

In summary, when the HIA data set is clean, that is, all the molecules undergo passive permeability mechanism, HIA can be predicted with a RMSE as low as 12%-16%. The most relevant descriptors to HIA are PSA, logD, logP, etc. 

Let us take the exposure packages as an example technically, most of these assays are highly automated, require small amount of compounds and have a brief cycle time. Scientifically, they fulfill requirements to predict exposure by addressing the three major contributing factors solubility, passive permeability and metabolic (hepatic) clearance. These type of packages are ideal to explore or diagnose scaffold characteristics and define project flowcharts. They can be used repeatedly to test newly synthesized compounds and guide SAR. A number of compounds within a... 

Figure 3.1 Correlation between passive permeability and in vivo BAV in Sprague Dawley rats (N=m). The PAMPA F(%) values in the y-axis were derived from the passive permeability measurements in a PAMPA assay [19] using a calibration curve with reference compounds of known fraction absorbed.

Figure 3.3 Impact of passive permeability on the efflux ratio (ER). Passive permeability (x-axis) was measured in a PAMPA assay [19]. Efflux ratios were derived from permeability measurements in a Caco-2 monolayer assay [44] and are expressed as the basolateral to apical/ apical to basolateral permeability ratios. The loading concentration was 5 XM in the PAMPA assay and 10 xM in the Caco assay. LC-MS/MS readout was used for both assays. The y-axis...

Although the impact of transporters on absorption appears to be moderate there is increasing evidence showing that transporters can significantly affect drug distribution, in particular for low permeable compounds. In this context transporter assays need to be prioritized for compounds with medium to low passive permeability. 

In addition it was also suggested that cell lines that have limited expression of transporters (e.g., 2/4/Al) are of use in understanding passive permeability. Saturation of transporters or inhibition can also be used to understand the contribution of passive permeation and active transport. 

---