Human permeability

Crystallinity aside, the two physical attributes of a drug that most control its skin permeability are its physical size and its lipophilicity [44,45]. When all extant human permeability coefficients (at the time over 90 compounds) were subjected to multiple linear regression by Potts and Guy using the following semi-empirical equation [45] ... 

The strategy of the preceding sections was based on predicting the permeabilities of drug compounds in the human jejunum. The rest of the intestinal tract has higher pH, and this needs to be factored in when considering models to predict not human permeabilities, but human absorption (see Fig. 2.3 and Table 7.2). 

In conclusion, the double-sink su m-P, PAMPA in vitro GIT assay seems to predict human absorption as well as in vivo human permeability measurements (see Figs. 7.66a,b) and in vitro Caco-2 permeability measurements (see Figs. 7.60 and 7.63), but at a lower cost and higher speed. 

Figure 5 Correlation of the fraction of dose absorbed with rat permeability. The rat permeability data were determined using the rat perfusion model. Considering the difference between the human permeability and the rat permeability, a scale factor was used to calculate the absorption number in Eq. (8). (Ref. 34 with kind permission from Plenum Publishing Corporation, New York.)...

Figure 10 The fraction of dose absorbed as a function of the effective human permeability. (---) Compartmental absorption and transit model (Eqs. (59) or (60)) (—) single-...

The buccal mucosa does serve as an alternative route for administering compounds systematically however, to ensure particular compounds are candidates for delivery across this biological tissue, preclinical screening is essential. While in vivo human permeability studies are ideal, due to their costs and associated issues, it is necessary to perform such screening in vitro. Assessment of compound permeability across porcine buccal mucosa has been widely used and can provide the preclinical biopharmaceutical scientist with much information relating to permeability, routes of transport, and effects of various chemical penetration enhancers. 

In a limited independent evaluation of GastroPlus , Hendriksen et al. [22] used literature data on solubility together with calculated human permeability values to predict the human Fabs for 21 drugs for which observed human FabS... 

The physiologically based model developed by Willman et al. [53, 54], for the prediction of both rat and human Fibs, was shown to be predictive for the human situation if passively transported compounds were studied. In their study, they used a semiempirical formula for the prediction of human permeability trained with a set of 119 passively transported drugs that did not show solubility or dissolution rate-limited absorption. 

The results of the simulations provide the user with simulated values for cell culture or PAMPA permeability and with estimates for human permeability in all areas of the human small and large intestine as well as allowing for plotting of the kinetics in all compartments of the simulation. 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

Figure 9.14 The effective permeabilities (Pefr, different clinically relevant concentrations to mean SD) of cimetidine in human jejunum at investigate saturation in any carrier-mediated two clinically relevant luminal concentrations. transport across the intestinal epithelium. No The rate and extent of intestinal absorption of difference in Pefr values between the two cimetidine have been widely discussed, and Fa concentrations was noted, and, togetherwith the for this drug has been estimated at around observation that human permeability in vivo is 75% [90, 91], It has been reported that cimetidine similar to permeability in the Caco-2 model (with is a substrate for both P-gp and/or organic cation low expression of carrier proteins), this suggests transporters (OCNT1 and OCNT2) [82, 92], We that passive diffusion is the dominant determined the human jejunal in vivo Pe - at two mechanism even for cimetidine [82],...

A cascade method was proposed using recursive partitioning and descriptors generated with a program called Algorithm Builder were used with a 800-compound training set [35]. Their predictions are 2-class models with Fs less than and more than 30%, respectively. As parameters, they use a combination of solubility, pifractions ionized, human permeability, P-gp substrate specificity, physicochemical properties, and various structural descriptors. This is an attempt to model the components of bioavailability and then to integrate them into an overall prediction (see further in Section 16.4). 

The relationships between animal and human permeability coefficients have been studied from the histological (Bronaugh et al., 1982) and empirical (Bronaugh et al., 1982 Marzulli et al., 1969 Wester and Noonan, 1980) perspectives. Most investigations reported that the skins of animals are different, usually more permeable, than human skin. In Appendix C, we review nine prior investigations or reviews of the relationship of permeability coefficients for animal and human skins. With one exception (Sato etal., 1989), none of these stodies recommended a quantitative approach for adjusting permeabifity coefficients from animal skins to represent human skin. 

Table A1 lists and Figure 15.1 shows 144 permeability coefficient values for 83 eompounds (83 fully validated and 61 excluded data points 45 fully validated compounds) measured in hairless mouse skin. All of the measurements excluded from this database were more than 90% ionized. Etorphine is distinguished on this figure because Vecchia and Bunge (2002b) used the fact that the human permeability coefficient is larger than the hairless mouse permeability coefficient to support exclusion of the measurement from the fully validated database for human skin. Notice that the hairless mouse permeability coefficient of etorphine is consistent with measurements for other cations, which was not the case with the human permeability coefficient for etorphine (Vecchia and Bimge, 2002b).

Figure 15.1 is similar to a comparable figure for the human skin database (see Figure 2 in Vecchia and Bunge, 2002b), suggesting that the underlying mechanism of dermal absorption is similar for both spedes. Several spedfic comparisons with the human permeability coefficients are noteworthy ... 

New databases were created consisting of chemicals for which fully validated measurements appeared in both the animal and human skin data sets. For compounds with multiple measurements, each measurement was independently adjusted for ionization (if necessary), and then all adjusted measurements for that compound were averaged. The ratio of the average animal and average human permeability coefficients was then calculated for each compound in the database of common chemicals. The logarithm of the ratios of the animal-to-human permeability coefficients were then linearly regressed as a function of MW and log using Equation 15.8. For all the databases studied here, the effects of both MW and log were... 

Table 15.3 Mean Values and Confidence Intervals of the Animal-to-Human Permeability Coefficient Ratios for Compounds Common to the Animal and Human Data Sets...

Various in vitro assays are widely available for profiling distribution, metabolism, and pharmacokinetics (DMPK, also referred to as ADME absorption, distribution, metabolism, and excretion). Such properties of molecules are measured to ultimately predict their in vivo behavior. The metabolic stability of molecules is assessed routinely in drug discovery units by way of medium- to high-through-put assays using hepatic microsomes or hepatocytes obtained from different species (usually rat and/or human). Permeability assays (e.g., utilizing Caco-2 or MDCK cells) together with an assessment of efflux potential are also useful to troubleshoot unexpectedly low cell activity or can help select candidates for subsequent in vivo studies. 

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