1,721,142 research outputs found
Ethanol-Inducible Cytochrome P450 2E1. Regulation, Radical Formation and Toxicological Importance.
No full text
Concerning Cytochromes P450: Role in the Metabolism and Toxicity of Drugs and other Xenobiotics . Edited by Costas Ioannides.
No full text
Implications of polymorphic cytochrome P450-dependent drug metabolism for drug development
Get PDFABSTRACT: 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. Pharmacokinetics and drug metabolism have been shown to be of greater importance during drug development today. It is evident that drugs that are too rapidly metabolized by drug-metabolizing enzymes mainly localized in the liver and the intestine are nonoptimal therapeutic candidates. In published overviews, it has been concluded that as many as 30 to 40% of the drugs undergoing clinical trials were withdrawn from further development due to unfavorable pharmacokinetic propertie
- …
