Reaction phenotyping correlation analysis

Correlation analysis is one of the four basic approaches to reaction phenotyping. It involves measuring the rate of drug metabolism by several samples of human liver microsomes (at least 10, according to the FDA) and correlating reaction rates with the variation in the level or activity of the individual CYP enzymes in the same bank of microsomal samples. This approach is successful because the levels of the CYP enzymes in human liver microsomes vary enormously from sample to sample (up to 100-fold), but with judicious selection of individual samples, they can vary independently from each other. 

Chemical and antibody inhibition represent the second and third approaches to reaction phenotyping. They typically involve an evaluation of the effects of known CYP enzyme inhibitors or inhibitory antibodies against selected CYP enzymes on the metabolism of a drug candidate by pooled human liver micro-somes. As in the case of correlation analysis, chemical and antibody inhibition experiments must be conducted with pharmacologically relevant concentrations of the drug candidate in order to obtain clinically relevant results. 

P450 metabolic reaction phenotyping to determine the relative contributions for specific P450 enzymes for metabolic clearance should use (1) chemical inhibition in collaboration with either (2) cDNA expressed systems, and/or (3) the utilization of reaction rate determination across a phenotypically characterized panel of microsomes from multiple individual donors (correlation analysis) (Ring and Wrighton, 2000). 

Corroler, D., Desmasures, N., Gueguen, M. (1998). Correlation between polymerase chain reaction analysis of the histidine biosynthesis operon, randomly amphfied polymorphic DNA analysis and phenotypic characterization of dairy Lactococcus isolates. Applied and Environmental Microbiology, 67, 2011-2020. 

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