Absorption potential

In 1985 a major step in the theoretical analysis of oral drug absorption phenomena took place [156], when solubility and dose were also taken into account for the estimation of the absorption potential A P of a drug apart from the pH-partition hypothesis related parameters (lipophilicity, and degree of ionization). According to this concept, the AP is related proportionally to the octanol/water partition coefficient Pc, the fraction of the un-ionized species, at pH= 6.5, and the physiological solubility cs of the drug and inversely proportional to the dose r/o  

The logarithmic expression in the definition of AP has no physicochemical basis and is used for numerical reasons only pH= 6.5 was selected as the representative pH of small intestines, where most of the absorption of drugs takes place. The incorporation of the terms Pc and fun in the numerator of (6.2) means that the pH-partition hypothesis governs gastrointestinal absorption. Plausibly, AP was considered proportional to solubility and inversely proportional to the dose in accord with classical dissolution-absorption considerations. The volume term V corresponds to the small-intestinal volume content, which was set arbitrarily 

The validity of the approach based on (6.2) was proven when the fraction of dose absorbed, Fa, was found to increase with AP for several drugs with a wide variety of physicochemical properties and various degrees of extent of absorption [156]. Additional support for the AP concept was provided by a 3-dimensional plot of Fa as a function of the ionization-solubility/dose term (fun/9) and the octanol/water partition coefficient Pc [157]. In fact, because of the recent interest in the apparent permeability estimates Papp measured in the in vitro Caco-2 monolayer system, it was suggested that Papp can replace the octanol/water partition coefficient Pc in (6.2) [157]. 

Although the AP concept is a useful indicator of oral drug absorption, its qualitative nature does not allow the derivation of an estimate for Fa. A quantitative version of Fa as a function of AP was published in 1989. It was based on the equilibrium considerations used for the derivation of AP and the fundamental physicochemical properties in (6.2) with the implied competing intestinal absorption and nonabsorption processes [158]. This quantitative AP concept relies on (6.3), where a nonlogarithmic expression for AP is used  

Based on physiological-physicochemical arguments, constraints were proposed for Pc, i.e., to be set equal to 1000 when Pc 1000 and 9 equal to 1 when 9 1. Equation (6.3) is, in reality, the first ever published explicit relationship between Fa and physicochemical drug properties. It was used to classify drugs according to their solubility, permeation, and ionization characteristics [158]. Moreover, (6.3) was monoparameterized  

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The absorption potential of carbon is given by its iodine number (IN). The IN is a measure of how many milligrams of iodine, present in a 0.02 N iodine solution, can be adsorbed by 1 gram of carbon. Usually the IN is between 850 and 1,200. 

At Novartis, so-called BioavailabiUty Radar Plots [44] are used to visually display the oral absorption potential of molecules. On these plots five important calculated descriptors (log P, molecular weight, PSA, number of rotatable bonds and water solubility score [45]) are displayed on the axes of a pentagonal radar plot and compared with predefined property limits (green area) which were determined by the analysis of marketed oral drugs. These plots provide an intuitive tool that displays multiple parameters as a single chart in a straightforward but informative way, providing visual feedback about the molecule s bioavailabiUty potential (Fig. 5.5). 

Fig. 12 Illustration of the Biopharmaceutical Classification System (BCS), which classifies drug absorption potential on the basis of aqueous solubility or membrane permeability. (Copyright 2000 Saguaro Technical Press, Inc., used with permission.)...

The Dressman-Amidon-Fleisher absorption potential concept [45], originally based on octanol-water partition coefficients, can be made more predictive, by using PAMPA permeabilities, instead of partition coefficients, for all the reasons discussed in Chapter 7. Such a scheme can be used to minimize false positive predictions of HIA. 

Dressman, J. B. Amidon, G. L. Fleisher, D., Absorption potential Estimating the fraction absorbed for orally administered compounds, J. Pharm. Sci. 74, 588-589 (1985). 

Zhu, C. Jiang, L. Chen, T.-M. Hwang, K.-K., A comparative study of artificial membrane permeability assay for high-throughput profiling of drug absorption potential, Eur. J. Med. Chem. 37, 399 107 (2002). 

Membrane diffusion illustrates the uses of Fick s first and second laws. We discussed steady diffusion across a film, a membrane with and without aqueous diffusion layers, and the skin. We also discussed the unsteady diffusion across a membrane with and without reaction. The solutions to these diffusion problems should be useful in practical situations encountered in pharmaceutical sciences, such as the development of membrane-based controlled-release dosage forms, selection of packaging materials, and experimental evaluation of absorption potential of new compounds. Diffusion in a cylinder and dissolution of a sphere show the solutions of the differential equations describing diffusion in cylindrical and spherical systems. Convection was discussed in the section on intrinsic dissolution. Thus, this chapter covered fundamental mass transfer equations and their applications in practical situations. 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

In reviewing the pH-partition hypothesis, it is apparent that it is an oversimplification of a very complex process. It does not consider one of the critical physicochemical factors, solubility. Low aqueous solubility is often the cause of the low bioavailability. To address this issue, Dressman et al. [28] developed an absorption potential concept that takes into account not only the partition coefficient but also solubility and dose. Using a dimensional analysis approach, the following simple equation was proposed ... 

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-... 

Figure 3 Correlation of the fraction of dose absorbed with the absorption potential. The calculation of the absorption potential is detailed in Dressman et al. [28], The quantitative form of the fraction of dose absorbed with the absorption potential was derived by Macheras and Symillides [29]. (Replot from Ref. 28 with kind permission from APhA, Washington, DC.)...

P Macheras, MY SymiUides. Toward a quantitative approach for the prediction of the fraction of dose absorbed using the absorption potential concept. Biopharm Drug Dispos 10 43-53, 1989. 

APsuv Absorption potential measured in small unilamellar vesicles (SUV)... 

Liposome partitioning of ionizable drugs can be determined by titration, and has been correlated with human absorption [102-104]. A new absorption potential parameter has been suggested, as calculated from liposome distribution data and the solubility-dose ratio, which shows an excellent sigmoidal relationship with human passive intestinal absorption (Eq. 2) [102, 103]. 

Here, APsuv is the absorption potential measured from the distribution in small unilamellar vesicles (SUV) at pH 6.8, the solubility was measured at pH 6.8 in simulated intestinal fluid, V is the volume of intestinal fluid, and dose is a mean single oral dose. Liposome partitioning is only partly correlated with octanol/water distribution. 

More than a decade ago, Caco-2 cells grown on permeable supports were introduced as an experimental tool for mechanistic studies of intestinal drug transport [1-4]. At the same time it was suggested that the Caco-2 model was suitable for screening intestinal drug permeability and predicting the oral absorption potential... 

Although, the pH-partition hypothesis has not been found to be universally applicable, it has resulted in the recognition of the important contribution of GI pH to permeability and to the dissolution rate of solid dosage forms. This theory does not consider the solubility of the drug, which is a critical physicochemical parameter in the oral absorption process. Dressman et al. [34] developed an absorption potential concept that takes the two parameters into account. The absorption potential is defined as... 

In an effort to address the poor membrane permeation of L-767,679, the benzyl ester pro-drug, L-775,318 was synthesized (Fig. 13.2) The latter compound exhibited significant lipophilicity (log P = 0.7) that was consistent with improved potential to cross the enterocyte membrane. However, this did not lead to a marked improvement in absorption potential (in the rat), as intestinal hydrolysis and counter-transport combined to prevent significant passage of the compound across Caco-2 cells and the rat gut. 

Fiserova-Bergerova V, Pierce JT, Droz PO. 1990. Dermal absorption potential of industrial chemicals criteria for skin notation. Am J Ind Med 17 617-635. 

Dressman et al. [13] developed a dimensionless absorption potential (AP) model based on the concept that the fraction of dose absorbed, assuming negligible luminal instability and first-pass metabolism, is a function of drug lipophilicity (log P0/w), solubility (Sw), and dose (D), as defined in Eq. 2.7. 

Dressman JB, Amidon GL and Fleisher D (1985) Absorption Potential— Estimating the Fraction Absorbed for Orally-Administered Compounds. J Pharm Sci 74 pp 588-589. 

Macheras PE and Symillides MY (1989) Toward a Quantitative Approach for the Prediction of the Fraction of Dose Absorbed Using the Absorption Potential Concept. Biopharm Drug Dispos 10 pp 43-54. 

Weinstein K, Kardos P, Strab R, Hidalgo U (2004) Cultured epithelial cell assays used to estimate intestinal absorption potential. In Borchardt RT, Kerns EH, Lipinski CA, Thakker DR, Wang B (Eds) Biotechnology Pharmaceutical Aspects Vol I Pharmaceutical Profiling in Drug Discovery for Lead Selection. AAPS Press, Arlington, pp 197-216. 

There are several cell monolayer models that are frequently used for the evaluation of drug permeability and absorption potential (Table 18.1). For a more detailed discussion, please refer to Chap. 8. Caco-2 cells (adenocarcinoma cells derived from colon) are the most extensively characterized and frequently used of the available cell lines [5-9], A unique feature of Caco-2 cells is that they undergo spontaneous enterocyte differentiation in cell culture. Unlike intestinal enterocytes, Caco-2 cells are immortalized and replicate rapidly into confluent monolayers. When the cells reach confluency during culture on a semi-porous membrane, they start to polarize and form tight junctions, creating an ideal system for permeability and transport studies. During the past decade, use of... 

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