Oral quantitative prediction

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

Kohda-Shimizu R, Li Y, Shitara Y. et al Oral absorption of cephalosporins is quantitatively predicted from... 

It was time for our first major re-think. Basically we had shown that our general medicinal chemistry approach to oral activity had been successful. These more lipophilic chromones were indeed being absorbed from the gastro-intestinal tract and reaching their required site of action, but we concluded that one could not use the rat PCA test, or indeed any of our newly developed tests, in a quantitatively predictive sense, for the identification of compounds which would be active anti-asthmatic agents, of the cromolyn type, in humans. I suspect that others have more recently come to the same conclusion about the PCA test, following the clinical evaluation of their own selected compounds. 

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-... 

L. X., Predicting human oral bioavailability of a compound development of a novel quantitative structure-bioavailability relationship, Pharm. 

As most drugs are preferably given orally, absorption which is complete, consistent and predictable is desirable. Although it may be possible from solubility, lipophilicity, pKa, molecular size, and animal data to make some prediction about likely absorption, only a study in humans will give quantitative data as the mechanisms of drug absorption are complex and still incompletely understood (Washington et al., 2001). It may be helpful here to distinguish between the terms absorption and bioavailability. ... 

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding the absorption of di-/ -octylphthalate in humans and animals following inhalation and dermal exposure. Information on absorption in humans following oral exposure is not available. There are studies that suggest oral absorption of di-/ -octylphthalate occurs in animals (Albro and Moore 1974 Oishi 1990 Poon et al. 1995) however, quantitative information is lacking. Additional information, primarily quantitative data, on absorption of di-/ -octy lphthalate for all routes of exposure is needed to understand and predict effects. 

Andrews CW, Bennett L and Yu LX (2000) Predicting Human Oral Bioavailability of a Compound Development of a Novel Quantitative Structure-Bioavailability Relationship. Pharm Res 17 pp 639-644. 

Andrews, C.W., Bennett, L., Yu, L.X. Predicting human oral bioavailability of a compound development of a novel quantitative structure-bioavailability relationship. Pharm. Res. 2000, 17, 639 4. 

Absorption, Distribution, Metabolism, and Excretion. Levels of cresols in blood were obtained from a single case report of a dermally exposed human (Green 1975). Data on the toxicokinetics of cresols in animals were contained in two acute oral studies that provided only limited quantitative information on the absorption, metabolism, and excretion of cresols (Bray et al. 1950 Williams 1938). A more complete oral toxicokinetics study, in addition to studies using dermal and inhalation exposure, would provide data that could be used to develop predictive pharmacokinetic models for cresols. Inclusion of several dose levels and exposure durations in these studies would provide a more complete picture of the toxicokinetics of cresols and allow a more accurate route by route comparison, because it would allow detection of saturation effects. Studies of the tissue distribution of cresols in the body might help identify possible target organs. 

There are several properties of a chemical that are related to exposure potential or overall reactivity for which structure-based predictive models are available. The relevant properties discussed here are bioaccumulation, oral, dermal, and inhalation bioavailability and reactivity. These prediction methods are based on a combination of in vitro assays and quantitative structure-activity relationships (QSARs) [3]. QSARs are simple, usually linear, mathematical models that use chemical structure descriptors to predict first-order physicochemical properties, such as water solubility. Other, similar models can then be constructed that use the first-order physicochemical properties to predict more complex properties, including those of interest here. Chemical descriptors are properties that can be calculated directly from a chemical structure graph and can include abstract quantities, such as connectivity indices, or more intuitive properties, such as dipole moment or total surface area. QSAR models are parameterized using training data from sets of chemicals for which both structure and chemical properties are known, and are validated against other (independent) sets of chemicals. 

Absorption, Distribution, Metabolism, and Excretion. The database for inhalation and dermal absorption of silver compounds in humans consists primarily of qualitative evidence from occupational case studies. Limited quantitative information exists on the oral absorption of silver compounds in humans. Research into the quantitative absorption of various silver compounds following relevant exposure routes would be useful to better predict the potential for toxic responses to particular silver compounds in humans. 

The only information that exists regarding distribution of silver in humans comes from an accidental exposure to an unknown quantity of radiolabeled silver metal dust. The distribution of various silver compounds is known in animals following inhalation and intravenous exposure only qualitative information exists for oral or dermal exposure. Quantitative data on the distribution of various silver compounds following oral and dermal exposure would be useful when predicting the distribution of silver following exposure to specific silver compounds in humans. 

D. A. Paterson, R. A. Conradi, A. R. HUgers, et al. A nonaqueous partitioning system for predicting the oral absorption potential of peptides. Quantitative Structure-Action Relationships, 13, 4-10 (1994)... 

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