ADME studies validation

The first set of information generated from the ADME studies are the overall plasma profiles of total radioactivity (TRA) versus time which is compared to the plasma profile of parent versus time measured by a validated LC/MS/MS assay. For those drugs where the parent is the major component at all time points in plasma, the total radioactivity profile usually parallels the profile of the parent. Metabolie profiles of plasma samples generated at different time points by high-performance liquid chromatography (HPLC) analysis followed by radioactivity and mass spectrometric detection provide exposure-related information for parent and metabolites in humans and animal species. In addition, this profile provides information about metabolites that humans are exposed to and how this compares to exposures in animal species. 

The ADM is valid for studying the interactions of herbicides with other herbicides or nonherbicides that exhibit similar action. Under the assumptions of the ADM, the growth responses of a test plant to the joint application of two components of a herbicide mixture are equated to the sum of the responses to each chemical tested separately.Thus, the predicted dose-response relationships for a herbicide mixture using the ADM are such that if one component of the mixture is replaced at a constant proportion by the other, the predicted response remains unchanged. Methods developed for the prediction of plant responses to herbicide mixtures using the ASM include the isobole method, the ANOVA method, and the two-parameter method. " ... 

Calculation of ADME predictions is now routine and often high throughput. However, unlike many published studies in which calculated properties are validated with experimental data for a diverse collection of molecules, for virtual small-molecule libraries, there are usually no physical data to validate the predictions. Often, the molecules that are the subject of calculation are dissimilar to those molecules used to develop prediction tools. As a result, one is usually looking for trends in the prediction as a function of the selection of specific diversity reagents around a common core or scaffold. Thus, it is important to consider predicted molecular properties with care and to interpret the results with the proper level of expectation. 

Fig. 3.1 Stairway to drug discovery. The drug discovery process as modeled here is not necessarily a linear process. Novel potential biopharmaceuticals (e.g., siRNAs) used in early steps of target identification and validation can, in principle, skip the next steps and be tested directly in ADME/tox-icity studies (see Part VI11, Chapter 4). ADM E, Adsorption, Distribution, Metabolism, and Excretion HTS, high-throughput screening.

In the first study, we tried to examine the validity of Gal-CHP liposome enclosing Adriamycin (Gal/CHP Lip-ADM). The radio-labeled CHP Lip or Gal/CHP Lip were added to cultured AH66 rat liver cancer cells in vitro. One hour later, the uptake of radio-labeled Gal/CHP Lip in AH 66 was the highest among all the tested liposomes. Athymic mice, which AH66 were subcutaneously transplanted, were intravenously administered free Adriamycin (ADM), conventional liposome enclosing... 

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