药物代谢PPTDrugMetabolism3.pptVIP

Drug Metabolism S.P. Markey Laboratory of Neurotoxicology NIMH, NIH Evolution of Drug Metabolism As a SciencePost WWII Pioneers Richard Tecwyn Williams – Great Britain 1942, worked on the metabolism on TNT with regard to toxicity in munitions workers; due to the war he assembled teams to work on metabolism of sulfonamides, benzene, aniline, acetanilide, phenacetin, and stilbesterol Developed concept of Phase 1 Phase 2 Reactions. Biotransformation involves metabolic oxygenation, reduction, or hydrolysis; result in changes in biological activity (increased or decreased) Second phase, conjugation, in almost all cases resulted in detoxication. Evolution of Drug Metabolism As a SciencePost WWII Pioneers Bernard B. Brodie, U.S. NYU and Laboratory of Industrial Hygiene, NYC 1949 – Metabolic fate of acetanilide and phenacetin in man (with Julius Axelrod) 1950s, NIH – pioneering studies on all aspects of drug metabolism; esp. reserpine, serotonin;hexobarbital tolerance 1952 – R.T. Williams spent 6 months at NIH; subsequently many students went between both labs (Richard Adamson, James Gillette, and Sidney Udenfriend) 1950s, Brodie lab developed the spectrophotofluorimeter (Robert Bowman) Drug Metabolism Liver Microsomal System Oxidative Reactions: Cytochrome P450 mediated Examples Formation of an inactive polar metabolite Phenobarbital Formation of an active metabolite By Design: Purine pyrimidine chemotherapy prodrugs Inadvertent: terfenadine – fexofenadine Formation of a toxic metabolite Acetaminophen – NAPQI Electron flow in microsomal drug oxidizing system Cytochrome P450 Isoforms (CYPs) - An Overview NADPH + H+ + O2 + Drug ? NADP+ + H2O + Oxidized Drug Carbon monoxide binds to the reduced Fe(II) heme and absorbs at 450 nm (origin of enzyme family name) CYP monooxygenase enzyme family is major catalyst of drug and endogenous compound oxidations in liver, kidney, G.I. tract, skin, lungs Oxidative reactions require the CYP heme protein, the red