Enzyme surrogate

H. Use of Surrogate Enzymes Can Lead to Important Insights, But Optimization Requires the... 

Liver microsomes from alternative animal sources have been used as in in vitro surrogate for HLMs [82,83]. The enzymes produced from animal sources are similar to their human... 

Sometimes it is not possible to measure the direct effect of the drug. Endpoints or surrogate biomarkers are used to monitor the pharmacodynamics and pharmacokinetics of the drug. These markers may be changes in blood pressure, cholesterol level, concentrations of certain enzymes, proteins, blood glucose levels, and similar factors (see Table 6.2 for serum tumor markers and Appendix 7 for general biomarkers). 

Use of surrogate enzymes can lead to important insights As described above in the Case Study, when the target enzyme is difficult to obtain or crystallize, a related enzyme can be used to provide insights in the design of novel ligands. 

The Rh-BIPHEPHOS-catalyzed cyclohydrocarbonylation has also been successfully applied to the rapid synthesis of a variety of l-azabicyclo[X.Y.O]alkane amino acids, which serve as conformationally restricted dipeptide surrogates for enzyme inhibitors and receptor antagonists, directly from dehydrodipeptide substrates (Scheme Reaction... 

Use of a surrogate end point that is quick and easy to obtain Permeation experiments using a radiolabeled, fluorescent, HPLC-detectable, or radio immuno assay/enzyme linked immuno sorbent assay-detectable marker necessitate the need of extensive sample handling and sample analysis. This accentuates the cost of sample analysis and overall time spent in characterizing the efficacy of formulations. Furthermore, current state of the art fluidics systems put a fundamental limit on the number of samples handled in a given time. 

Biocompatibility of injectable formulations with tissues can be tested by observing microscopic histology of the tissues so exposed, or by using erythrocyte hemolysis as a surrogate for these other tissues. Alternatively, one can measure the level of the cytosolic enzyme creatine phosphokinase that is released from damaged tissues (18). 

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