gADME: Characterization of CYP2D6 activity of mutant proteins using control substrates and CNS-active drugs

Genetic variability of drug metabolism is a recurrent problem in drug development. Cytochrome P450 (CYP) is a family of enzymes that are primarily responsible for the oxidative metabolism of most pharmaceuticals. Of the over fifty isoforms of CYPs encoded by the human genome, ten are responsible for the majority of drug metabolism. CYP2D6 isoforms, though they account for only 2% of the total CYP enzymes in the liver, are responsible for the oxidative metabolism of 30% of the approved drugs including a number of psychiatric drugs. More than 100 different genetic variants of CYP2D6 have been described, including a number that involve alterations in the coding sequence for the CYP2D6 protein. We have characterized a number of purified CYP2D6 mutant proteins and characterized their activity against the standard substrates bufuralol, dextromethorphan, and debrisoquine. We have measured the metabolic activity of this panel against a set of drugs composed of antidepressants (TCAs and SSRIs), antipsychotics, and other psychiatric drugs. Through this analysis, we have gained insight into the underlying mechanism of phenotypic variation in psychiatric drug metabolism. This information can be utilized in stratifying populations of potential responders and non-responders in clinical studies and in the market, thus increasing the chances of the drug candidate to be successful in clinical studies and in the marketplace. This is particularly important for CNS drugs, where failure in the clinic is particularly high, compared to other therapeutic areas, and any tool that increases the probability of success has a potential to have a large impact on the outcome.