Human oral absorption data

Instead of using surrogate measures for oral absorption with a lipophilicity or permeability assay in vitro, oral absorption can also be estimated in silico by using human oral absorption data from the literature [16]. These data are rather sparse because oral absorption is not systematically measured in clinical trials. The data are also skewed toward high absorption compounds. In addition, interindividual variability is important, about 15%. Of course, absorption can also depend on dose and formulation. Therefore, early estimates are only rough guides to get the ballpark right. 

Poorly absorbed compounds have been identified as those with a PSA >140 A2. Considering more compounds, considerably more scatter was found around the sigmoidal curve observed for a smaller set of compounds [71]. This is partly due to the fact that many compounds not only show simple passive diffusion but are also affected by active carriers, efflux mechanisms involving P-glycoprotein (P-gp) and other transporter proteins, and gut wall metabolism. These factors also contribute to the considerable interindividual variability of human oral absorption data. A further refinement in the PSA approach is expected to come from taking into account the strength of the hydrogen bonds, which in principle already is the basis of the HYBOT approach [60-62],... 

Polybrominated Biphenyls. Quantitative oral absorption data in humans were not located, but reports of increased levels of PBB residues in tissues and serum of individuals accidentally exposed to contaminated food indicate that gastrointestinal absorption of PBBs had occurred (Eyster et al. 1983 Humphrey and Hayner 1975 Landrigan et al. 1979 Miceli et al. 1985 Wolff et al. 1982). 

Yoshida F, Topliss JG (2000) QSAR Model for drug human oral bioavailability. J Med Chem 43 2575-2585 Zhao YH, Le J, Abraham MH et al. (2001) Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci 90 749-784... 

Figure 9.8 Parallel artificial membrane permeability assay Papp values versus literature values, for human oral absorption, for a set of 93 drugs. Note circled areas, where PAMPA data were not predictive, including 45, griseofulvin, for which bioavailability is known to be very formulation-dependent. (Reprinted with permission from Zhu, C., et al. A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur. J. Med. Chem. 2002, 37, 399 07, copyright 2002, Elsevier).

We have long been Interested in the possibility that the cardiovascular effects of carboxylic lonophores could be harnessed to provide new drugs for the treatment of disease states such as heart failure and shock. There may, however, be subpopulations of man for whom lonophores may be particularly toxic. For example, a toxic Interaction between monensln and digitalis on the dog heart has been reported (37). Our oral absorption data do Indicate that If a useful human therapeutic application can be established, lonophores could be administered as drugs orally. 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

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. ... 

Also included in in vivo data is a set of human (90% of drugs) and animal pharmacokinetic (30% of drugs) data. While the in vitro data are generated in-house (Cerep), pharmacokinetic data are gathered from the literature. A variety of different parameters are covered including absolute bioavailability, oral absorption, clearance, volume of distribution, half-life, protein binding and excretion information. 

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. 

Different formulation principles, dosage forms, and DDSs are commonly evaluated in animal models, and attempts are made to predict human absorption on the basis of such studies.80 Human studies are also conducted in some cases to confirm predictions from animal models. Chiou et a 1.81,82 demonstrated that there is a highly significant correlation of absorption (r2 = 0.97) between humans and rats with a slope near unity. In comparison, the correlation of absorption between dog and human was poor (r2 = 0.512) as compared to that between rat and human (r2 = 0.97). Therefore, although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, one may need to exercise caution in the interpretation of data obtained. 

Quantitative absorption studies are not available for 1,4-dichlorobenzene in either humans or animals. This compound has some structural similarities to benzene and the smaller chlorinated aliphatics, and is thus assumed to be 100% absorbed when administered orally. Available data on 1,4-dichlorobenzene itself shows that under specific conditions, about 20% was absorbed via inhalation during a 3-hour exposure period. The potential for dermal absorption has not been assessed. 

Figure 8. Heat map of a cluster of BioPrint compounds with similar in vitro ADME profiles. Eight ADME assays are clustered on the X-axis and 8 compounds are clustered on the Y-axis. Normalized data range from 0 (blue-green) to 2 (red). Clustering is performed using Pearson correlation and complete linkage using normalized dataset. Where available in literature, human in vivo oral absorption (oa) and oral bioavailability (ba) values (%) are presented after the compound name.

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 is considerably less information available on the toxicology of HDl after oral exposure compared to the data available on the inhalation toxicology of HDl discussed in the previous section of this profile. Clearly, inhalation is the major route of occupational exposure to HDl however, given exposure routes such as the lung mucocilliary clearance pathways, a very small amoimt of HDl could eventually enter the gastrointestinal tract and be presented for absorption, with possible systemic effects. Most of the information available on the oral absorption of HDl is about relatively large doses of HDl administered to laboratory animals, with no information located on the health effects of HDl in humans after oral exposure. 

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