Implications of polymorphic cytochrome p450-dependent drug metabolism for drug development.

The main part of human cytochrome P450-dependent drug metabolism is carried out by polymorphic enzymes that can cause abolished, quantitatively or qualitatively altered, or enhanced drug metabolism. Ultrarapid metabolism is due to stable duplication, multiduplication, or amplification of active genes. Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. The polymorphic enzymes create a problem for the drug industry because of the extensive interindividual variability in the metabolism of candidate drugs that are substrates for such enzymes. The new area for lead generation has a more preclinical emphasis and involves combinatorial chemistry in conjunction with high-throughput-based analysis of thousands of substances with respect to their absorption, metabolism, and excretion characteristics. The outcome is that companies drop substrates for polymorphic enzymes at an early stage in development, which will of course create fewer problems with polymorphic enzymes in the future. The risk is that very valuable candidates, which cannot be replaced easily, never come out on the market. The alternative, however, of using the patient's genotype as a basis for individualized drug treatment constitutes, in light of rapid methodological developments, a very feasible approach to safer and more efficient drug therapies.