Absorption potential concept

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. 

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-... 

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. 

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... 

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. 

PBPK approaches are classified into three categories [82] quasiequilibiium models, steady-state models, and dynamic models. The classification of these models is based upon their dependence on spatial and temporal variables. The quasiequi-librium models, which are independent of spatial and temporal variables, include the p/f-partition hypothesis and absorption potential concept. The steady-state models are limited to prediction of the extent but not the rate of oral drag absorption. The dynamic models consider spatial and temporal variables and can predict both the rate and extent of oral drag absorption. The dynamic models include dispersion... 

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. 

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 ... 

Recently the same problem has been reanalyzed by Dicus et al. [86], and indeed they confirmed that the survival probability deviates from exponential at long times. This model and its variants have been applied to study the effect of a distant detector (by adding an absorptive potential) [87], anomalous decay from a flat initial state [44], resonant state expansions [3], initial state reconstruction (ISR) [58], or the relevance of the non-Hermitian Hamiltonian concept (associated with a projector formalism for internal and external regions of space) in potential scattering [88]. In Ref. [88] the model was extended to a chain of delta functions to study overlapping resonances. 

All the preceding mechanisms of the carrier packet spread and transit time dispersion imply that charge transport is controlled by traps randomly distributed in both energy and space. This traditional approach completely disregards the occurrence of long-range potential fluctuations. The concept of random potential landscape was used by Tauc [15] and Fritzsche [16] in their models of optical absorption in amorphous semiconductors. The suppressed rate of bimolecular recombination, which is typical for many amorphous materials, can also be explained by a fluctuating potential landscape. 

While the stability of the monolayer Pt alloy catalyst concept was initially unclear and therefore threatened to make the monolayer catalyst concept a questionable longer term solution, a very recent discovery seems to lend support to the claim that Pt monolayer catalyst could be made into stable catalyst structures Zhang et al. [94] reported the stabilizing effect of Au clusters when deposited on top of Pt catalysts. The presence of Au clusters resulted in a stable ORR and surface area profile of the catalysts over the course of about 30,000 potential cycles. X-ray absorption studies provided evidence that the presence of the Au clusters modified the Pt oxidation potentials in such a way as to shift the Pt surface oxidation towards higher electrode potentials. 

---