Permeability mass balance

When membrane retention of the solute needs to be considered, one can derive the appropriate permeability equations along the lines described in the preceding section Eqs. (7.1)—(7.3) apply (with P designated as the effective permeability, Pe). However, the mass balance would need to include the membrane compartment, in addition to the donor and acceptor compartments. At time t, the sample distributes (mol amounts) between three compartments ... 

The membrane permeabilities Pm may be converted to intrinsic permeabilities P(h when the pKa is taken into consideration. An ionizable molecule exhibits its intrinsic permeability when it is in its uncharged form and there is no water layer resistance. The relationship between Pm and P0 is like that between the pH-dependent apparent partition coefficient (log Kd) and the true partition coefficient (log Kp), respectively. This relationship can be rationalized by the mass balance. Take, for example, the case of a monoprotic acid, HA. The total substance concentration is... 

Although the pH-partition hypothesis and the absorption potential concept are useful indicators of oral drug absorption, physiologically based quantitative approaches need to be developed to estimate the fraction of dose absorbed in humans. We can reasonably assume that a direct measure of tissue permeability, either in situ or in vitro, will be more likely to yield successful predictions of drug absorption. Amidon et al. [30] developed a simplified film model to correlate the extent of absorption with membrane permeability. Sinko et al. [31] extended this approach by including the effect of solubility and proposed a macroscopic mass balance approach. That approach was then further extended to include facili-... 

According to the FDA BCS guideline, measurements of the permeability and fraction dose absorbed of a drug can be made by mass balance, absolute bioavailability or intestinal perfusion methods. The intestinal permeability of a drug can be determined by ... 

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

Estimating Effective Intestinal Permeability Coefficient Using a Mass Balance Approach... 

Refinement and expansion of these steady-state mass balance approaches has led to the development of dynamic models which allow for estimation of the fraction absorbed as a function of time and can therefore be used to predict the rate of dmg absorption [37], These compartmental absorption and transit models (CAT) models have subsequently been used to predict pharmacokinetic profiles of drugs on the basis of in vitro dissolution and permeability characteristics and drug transit times in the intestine [38],... 

Chemical species can transfer between phases, and this represents the coupling between the mass-balance equations. This geometry looks like a membrane reactor in which a permeable area A (dashed lines) separates the phases, but all multiphase reactors can be described by this notation. 

The apparent permeability of 11 test compounds was measured in the presence and absence of human serum albumin in the donor compartment, and by solving the differential equations describing the kinetics of membrane permeability, membrane retention and protein binding, the authors were able to obtain the Kd. With the protein in solution rather than immobilized and without the need for mass balance or equilibrium conditions, this approach provides an attractive alternative to existing methods with the potential to be applied to an array of other soluble proteins. 

The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans and directly on measurements of the rate of mass transfer across human intestinal membrane. Alternatively, nonhuman systems capable of predicting the extent of drug absorption in humans can be used (e.g., in vitro epithelial cell culture methods). In the absence of evidence suggesting instability in the gastrointestinal tract, a drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. 

The permeability class of a drug substance can be determined in human subjects using mass balance, absolute BA, or intestinal perfusion approaches. Recommended methods not involving human subjects include in vivo or in situ intestinal perfusion in a suitable animal model (e.g., rats), and/or in vitro permeability methods using excised intestinal tissues, or monolayers of suitable epithelial cells. In many cases, a single method may be sufficient (e.g., when the absolute BA is 90%... 

The permeability is a property of the membrane material of the separating layer, whereas the permeance is also a property of the product membrane in its entirety considering thickness, the eventual support, defects, and so on. For this reason, the permeance will be used instead of permeability in subsequent mass-balance equations. 

Systemic bioavailability is the product of fraction of dose absorbed (/a), fraction of dose escaping gut metabolism (/g), and fraction of dose escaping first-pass metabolism (F ). Permeability class is based upon /a, which may be estimated either in vivo or in vitro by direct measurement of mass transfer across human intestinal epithelium. In vivo methods include (i) mass balance studies using unlabeled, stable-isotope labeled, or a radiolabeled drug substance (ii) oral bioavailability using a reference intravenous dose or (iii) intestinal perfusion studies either in humans or an acceptable animal model. Suitable in vitro methods involve the use of either excised human/animal intestinal tissues or cultured epithelial monolayers. All of these methods are deemed appropriate for drugs whose absorption is controlled by passive mechanisms. 

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