Skewed dosing

The major urinary metabolite of di(2-ethylhexyl) adipate, 2-ethylhexanoic acid, has been shown to be an appropriate marker for biological monitoring of dietary di(2-ethylhexyl) adipate intake (Loftus etal., 1993, 1994). A limited population study in the United Kingdom was undertaken to estimate the daily intake of di(2-ethylhexyl) adipate following intake of a mean dose of 5.4 mg di(2-ethylhexyl) adipate presented with food. The study involved the determination of the urinary metabolite, 2-ethyl-hexanoic acid (24-h mine sample) in 112 individuals from five geographical locations. A skewed distribution with a median value for the daily intake of 2.7 mg was determined (Loftus et al., 1994). This value is about one third of the indirectly estimated maximum intake of 8. 2 mg per day. The probability of a daily intake in excess of 8.2 mg in the limited population (112 individuals) was calculated to be 3% (Loftus etal, 1994). 

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. 

The box plot has proved to be a popular graphical method for displaying and summarizing univariate data, to compare parallel batches of data, and to supplement more complex displays with univariate information. Its appeal is due to the simplicity of the graphical construction (based on quartiles) and the many features that it displays (location, spread, skewness, and potential outliers). Box plots are useful for summarizing distributions of treatment outcomes. A good example would be the comparison of the distribution of response to treatment at different dose levels or exposure (as measured by area under the plasma concentration-time curve) as in Figure 37.3. 

Examination of the univariate distribution of 5-FU clearance revealed it to be skewed and not normally distributed suggesting that any regression analysis based on least squares will be plagued by non-normally distributed residuals. Hence, Ln-transformed 5-FU clearance was used as the dependent variable in the analyses. Prior to analysis, age was standardized to 60 years old, BSA was standardized to 1.83 m2, and dose was standardized to 1000 mg. A p-value less than 0.05 was considered to be statistically significant. The results from the simple linear regressions of the data (Table 2.4) revealed that sex, 5-FU dose, and presence or absence of MTX were statistically significant. 

If the density gradient has become faulty for one reason or another, the zones may be skew at the completion of electrofocusing. They will then be impossible to separate by elution. To repair such a fsdlure the column should be eluted into a fraction collector in the usual way. The fractions should then be carefully added to the column in the proper order. If the column is now electrofocused again, the result should be satisfactory. The density gradient will be steady agmn. Since the pH-gradient is for the most part established and the sample proteins are also fairly dose to their final positions in the column, this second run will take much less time. 

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