Comparison of metabolic profiles

Interspecies comparison of metabolic profile to select species for preclinical studies (safety pharmacology)... 

Comparison of Metabolic Profiles In Urine. Llyer aml Kldfigj The metabolic profiles of liver and kidney were compared with that of urine. The comparison was done using the analysis of the extracts on two reverse phase HPLC systems. Based on the comparison of RRTs, It was evident that the metabolites found In liver and kidney were also found In the urine. 

A major use of radiolabeled drugs in the in vivo situation is for metabolic profiling. These studies can be utilized to investigate interspedes comparisons of metabolic profiles in plasma urine and feces (or bile) in conjunction with toxicology or carcinogenicity studies or for performing definitive metabolite profiling in human ADME studies. 

An example of a metabolic profile from the MS/MS analysis of a confirmed infant with PKU and MCAD deficiency is shown in Figure 13.14. Comparison of these profiles can be made with the normal profiles shown in Figure 13.12. The profiles shown in Figure 13.14 include only the abnormal NL 102 full-scan function for PKU and the Pre 85 full-scan function for MCAD deficiency. These profiles are part of a visual qualitative inspection of results which is often called metabolic profiling. What is not seen in the printout is a list of quantitative results. Which each analysis, most MS data processing system will provide a tabular listing of each metabolite, its concentration, and whether it is above or below a particular threshold as shown in Figure 13.13. Often, these results are included in a printout with the abnormal mass spectrum so that both quantitative and qualitative inspection can be made. In the case of the spectra... 

Figure 3.4 GC/MS metabolic profile of a polar M. truncatula root extract that provides the identification for many of the root components. Individual components are identified by matching their mass spectra to those in databases or by comparison with authentic samples. Using this approach we have identified a large number (>130 currently) of primary metabolites in M. truncatula.

These in vivo and in vitro human metabolism studies indicate that pyrethroids undergo rapid metabolism and elimination as observed in rats, and qualitative metabolic profiles (e.g., kinds of metabolites) of pyrethroids are assumed to be almost the same between humans and rats, suggesting that a large database of animal metabolism of pyrethroids could provide useful information for the evaluation of behavior of pyrethroids in humans. Nowadays, human pesticide dosing studies for regulatory propose are severely restricted in the US, and thus detailed comparison of in vitro metabolism (e.g., metabolic rate constants of pathways on a step-by-step basis) using human and animal tissues could be an appropriate method to confirm the similarity or differences in metabolism between humans and animals. 

In comparison with other measurement methods, NMR has important strengths. Its great virtue is its noninvasive nature, allowing one to obtain spatially resolved metabolic profiles and to investigate metabolomics in vivo. 10 There is little or no sample preparation. It is nondestructive. It is information-rich with regard to the determination of molecular structures because it can detect different chemical groups of metabolites simultaneously. 

Benowitz ML, Jacob P 3rd, Fong I, Gupta S (1994) Nicotine metabolic profile in man comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268 296-303 Benowitz NL, Perez-Stable EJ, Eong 1, Modin G, Herrera B, Jacob P 3rd (1999) Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 291 1196-1203 Benowitz NL, Griffin C, Tyndale R (2001) Deficient C-oxidation of nicotine continued. Chn Pharmacol Ther 70 567... 

When data are available to enable comparison of the plasma concentration time profile after single administration with that after repeated administration, this would enable determination of whether the substance has time dependent kinetics (due to induction of metabolism, inhibition of metabolism, and/or accumulation and saturation of processes involved in distribution, metabohsm, and excretion). 

When a compound is administered by a route other than intravenously, the plasma level profile will be different, as there will be an absorption phase, and so the profile will be a composite picture of absorption in addition to distribution and elimination (Fig. 3.26). Just as first-order elimination is defined by a rate constant, so also is absorption kab. This can be determined from the profile by the method of residuals. Thus, the straight portion of the semilog plot of plasma level against time is extrapolated to the y axis. Then each of the actual plasma level points, which deviate from this during the absorptive phase, are subtracted from the equivalent time point on the extrapolated line. The differences are then plotted, and a straight line should result. The slope of this line can be used to calculate the absorption rate constant kab (Fig. 3.26). The volume of distribution should not really be determined from the plasma level after oral administration (or other routes except intravenous) as the administered dose may not be the same as the absorbed dose. This may be because of first-pass metabolism (see above), or incomplete absorption, and will be apparent from a comparison of the plasma... 

Tirona, R., Schwab, A., Geng, W., and Pang, K., Hepatic clearance models Comparison of the dispersion and Goresky models in outflow profiles from multiple indicator dilution rat liver studies, Drug Metabolism and Disposition, Vol. 26, No. 5, 1998, pp. 465-475. 

If metabolism in animal models is extensive or the generated metabolite(s) is shown to have toxic effects, in vitro metabolism studies using isolated P-450 isozymes, tissue homogenates containing the microsomal fraction, hepatocytes, and liver slices are commonly conducted to determine if the extent of metabolism and the metabolite profile is similar for animals and humans. The results from these in vitro metabolism comparison studies can be used to select the animal models for definitive development studies that have similar metabolism profiles to humans. 

The four PBPK models that are highlighted in this section of the profile have each contributed to the overall understanding of the pharmacokinetics of benzene. For instance, the Medinsky model addresses species differences in benzene kinetics using mice and rats. The Travis model specifically addresses human pharmacokinetics of benzene in comparison to experimental animal data, whereas the Bois and Paxman model addresses the effect of exposure rate on benzene metabolism. Finally, the Sun model addresses the formation of hemoglobin-benzene derived adducts in the blood, as a tool in monitoring benzene exposure. Each of these models in discussed in detail below. 

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