Vitro to In Vivo Translation

We have used biokinetic approaches (defined as the study of uptake, movement and metabolism of compounds within target organisms) to try to address in vitro to in vivo translation in Syngenta. Studies have included uptake into the fungus, often using non-radiolabeled, LC-MS analytical techniques at this early stage. Metabolism, tracking loss ofthe parent compound, has been applied to understand 

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In Vitro to In Vivo Translation, Structure Based Design... 

The works of Diaz et al. (2013), Tarrant et al. (2015), Uppal et al. (2015), and Zabka et al. (2015) are recent examples of utilizing cell-based models to investigate toxicity observed in animal or clinical studies and to evaluate the in vitro to in vivo translation and cross species sensitivity to an identified toxicant. 

Poor translation of in vitro to in vivo activity (e.g., due to poor accessibility of the target, up-/downregulation of target or endogenous ligand or compensatory effects). 

Experimental Design Experimental design for both in vitro and in vivo translational studies is influenced by the endpoints that will be evaluated in clinical studies. The experimental design should also recognize that new endpoints may need to be evaluated in clinical trials. An example of a preclinical development program for a combined cell-based neo-organ product is presented in Table 35.10. 

A progression in the complexity of models (e.g., cell lines to explants) and from in vitro to in vivo testing is a prudent approach to solve mechanistic and translational problems. 

In eukaryotes, translation initiation is rate-limiting with much regulation exerted at the ribosome recruitment and ternary complex (elF2 GTP Met-tRNAjMet) formation steps. Although small molecule inhibitors have been extremely useful for chemically dissecting translation, there is a dearth of compounds available to study the initiation phase in vitro and in vivo. In this chapter, we describe reverse and forward chemical genetic screens developed to identify new inhibitors of translation. The ability to manipulate cell extracts biochemically, and to compare the activity of small molecules on translation of mRNA templates that differ in their factor requirements for ribosome recruitment, facilitates identification of the relevant target. 

Reported in vitro dissolution failures due to cross-linking of gelatin shells that did not result in bioinequivalence [42,45] serve as another set of examples, although based on a different mechanism, that suggests that significant in vitro differences do not necessarily translate to in vivo differences. 

Fraga CG. 2007. Plant polyphenols How to translate their in vitro antioxidant actions to in vivo conditions. IUBMB Life 59 308-315... 

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