Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics.
The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.
Pharmacokinetics and Drug Metabolism, Amgen, Cambridge, Massachusetts (R.S.F.); and Pharmacokinetics, Dynamics, and Metabolism, Pfizer, La Jolla, California (D.K.D.) rfoti@amgen.com.
Robert S
RS
Foti
Pharmacokinetics and Drug Metabolism, Amgen, Cambridge, Massachusetts (R.S.F.); and Pharmacokinetics, Dynamics, and Metabolism, Pfizer, La Jolla, California (D.K.D.).
Deepak K
DK
Dalvie
D065767:Activation, Metabolic; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000378:metabolism; D015262:Xenobiotics / Q000009:adverse effects / Q000493:pharmacokinetics*
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D014453:Glucuronosyltransferase; D015238:Sulfotransferases