Permeability compounds

Table 3). For example, arabinose and xylose differ from ribose only in the orientation of the 2 - and 3 -OH groups yet exhibit markedly different potencies. Whereas 9-(tetrahydrofuryl)-Ade ( SQ 22,536) and 9-(cyclopentyl)-Ade are without hydroxyl groups and are less potent, they offer metabolic and biochemical stability useful for many types of studies. It is, however, the removal of two of the hydroxyl groups, that elicits the largest improvement in inhibitory potency, in particular the 2, 5 -dideoxy- modification (Table 3). With these improvements in potency, these cell permeable compounds, in particular 2, 5 -dd-Ado, have become useful research tools and have been used to inhibit adenylyl cyclases and to lower cAMP levels and alter function in numerous studies in isolated cells or intact tissues. 

Substituent group Influence on membrane permeability Compound Example aa... 

Previously, the unstirred water layer (UWL) adjacent to the intestinal lining was considered to be the rate-limiting step for intestinal Peff of high-permeability compounds [27, 73], However, several in vivo studies have clearly reported that the thickness of this UWL is significantly thinner than was previously assumed, since... 

The VolSurf method was used to produce molecular descriptors, and PLS discriminant analysis (DA) was applied. The statistical model showed two significant latent variables after cross-validation. The 2D PLS score model offers a discrimination between the permeable and less permeable compounds. When the spectrum color is active (Fig. 17.2), red points refer to high permeability, whereas blue points indicate low permeability. There is a region in the central part of the plot with both red and blue compounds. In this region, and in between the two continuous lines, the permeability prediction is less reliable. The permeability model... 

The jejunal perfusion approach generates data which may be used to predict absorption/bioavailability and to establish in vivo-in vitro correlation (IVIVC) even for extended release (ER) products. If a dmg is transported mainly by passive diffusion and has a jejunal Peff higher than metoprolol (1.5 x 10-4 cm s 1 = high-permeability compound), it can be expected to be completely absorbed throughout the small and large intestine [5, 46]. 

Class II drugs, i.e., low-solubility/high-permeability compounds, are expected to have a dissolution-limited absorption. Thus, for these types of drugs an IVIVC... 

Accumulation/efflux studies can be performed on different cell systems or membrane vesicle preparations. In the accumulation assays, uptake of a probe over time, typically either fluorescent (e.g. calcein-AM (CAM) [25-27]) or radiolabeled, into the cell or membrane vesicles is measured in the presence or absence of a known P-gp inhibitor. As P-gp transports substrates out of the cells, the inhibition of the protein would result in an increase in the amount of the probe in the cell. Accumulation studies in cells that overexpress P-gp can be compared to those obtained in the parental cell line that does not have as high a level of P-gp expression. The probe in the absence of inhibitors shows lower accumulation in P-gp expressing cells than in P-gp deficient cells. Similarly, probe accumulation is increased under conditions where P-gp is inhibited such that the difference in accumulation in P-gp deficient and overexpressing cells, respectively, becomes smaller. Accumulation assays poorly distinguish substrates and inhibitors of P-gp and, as far as transport assays are concerned, are also influenced by a passive diffusion property of molecules [20]. In contrast to transport assays, both accumulation (i.e. calcein-AM assay) and ATPase assays tend to fail in the identification ofrelatively low permeable compounds as P-gp active compounds [20]. 

As noted earlier, the choice of species for experimentation is critical due to anatomical differences and it may also reflect species, as well as individual, differences in the expression/activity of transporter and metabolic proteins [43, 44], Since the fraction absorbed across buccal mucosa in vivo is not established for many compounds in different species including humans, the potential existence of a correlation between in vitro permeability coefficients in freshly isolated pig, dog, monkey, and human buccal mucosa was investigated (Figure 7.3). The correlation coefficient obtained for porcine and canine tissue was poor (0.65 and 0.67, respectively, at the 95% confidence level). Results for relatively high permeability compounds in porcine tissue resemble those previously reported where permeability coefficients were by an order of magnitude... 

Zhu and coworkers used hydrophilic filters (low protein binding PVDF) in their model [179]. This change in the setup resulted in a significant transport time reduction to 2 h (compared with more than 10 h for a hydrophobic filter) without loss of information for low permeability compounds. 

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. 

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. 

The applicability of PBPK models can be described in the context of the BDDCS classification [24]. PBPK models are very predictive for class 1 and class 2 compounds. However for poorly soluble compounds, the use of aqueous solubility is shown to be inadequate for reliable prediction of oral absorption in physiologically based models [7]. In such cases, it is recommended to use solubility measured in simulated intestinal fluids (FeSSIF, FaSSIF). Such data proved to be very relevant to simulate the oral absorption of BCS 2 (low solubility, high permeability) compounds [25]. 

There are three main sites of absorption skin (large surface area poorly vascularized not readily permeable) gastrointestinal tract (major site well vascularized variable pH large surface area transport processes food gut bacteria) lungs (very large surface area well vascularized readily permeable). Compounds may be administered by direct injection (i.p., i.m., s.c., i.v.). 

Beaumont, K., et al. 2003. Design of ester prodrugs to enhance oral absorption of poorly permeable compounds Challenges to the discovery scientist. Curr Drug Metab 4 461. 

Lipids may also have effects on gastric transit (in terms of delaying gastric emptying) and intestinal permeability (enhancing the absorption of poorly permeable compounds). These areas have been well covered in other texts [16-19],... 

A fraction of our in-house -8500 ATP-site competitor compounds have been profiled in a number of cellular assays for toxicity, solubility, and permeability. Nontoxic, soluble, permeable compounds have been gathered into a subset of the main library, which we call the validation library . The validation library currently... 

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