The potential pharmacological and toxicological impact of P450 screening.
Cytochrome P450 (CYP) proteins catalyze the majority of drug biotransformations and play a pivotal role in several homeostatic mechanisms. Perturbation of CYP activity can have profound effects on therapeutic efficacy and in extreme cases may lead to life-threatening toxicities. The trend towards front loading physicochemical properties, and drug metabolism and pharmacokinetics (DMPK), in an attempt to minimize the attrition within drug development, has been a concentrated effort on screens aimed at optimizing interactions with the CYP system. These include improving metabolic stability and minimizing the potential for drug-drug interactions associated with marked reductions (inhibition) or increases (induction) in CYP activity. Increased emphasis on the identification of individual CYPs responsible for drug metabolism is also a common theme, with the desire to provide early alerts to compounds cleared predominantly by polymorphic enzymes or isozymes which demonstrate marked inter-subject variability. These data may provide a rationale for individualized therapy in the near future. Such screens should see the establishment of large databases and better in silico (if not in cerebro) prediction of properties typically associated with successful marketed therapies.
Riley
R J
RJ
Department of Physical and Metabolic Science, AstraZeneca R&D Chamwood, Loughborough, Leicestershire, LE11 5RH, UK. rob.riley@astrazeneca.com
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions / Q000502:physiology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System