药物分析-第三部分：药物代谢分析-药动学和药物代谢ADME-Tox.pptxVIP

;ADME-Tox;实验基本要求与方法;The time course of drug plasma concentrations;;Distribution;Metabolism;Excretion;Toxicity;;Metabolic Reaction;Phase I transformations;Chemical view of oxidation by CYP 450;Phase I transformations;CYPs MW in the range of 45-60 kDa. Most of the drug metabolizing enzymes are in CYP 1, 2, 3 families . Multiple CYP gene families have been identified in humans, and the categories are based upon protein sequence homology CYP3A4 is very common to the metabolism of many drugs; its presence in the GI tract is responsible for poor oral availabilty of many;Families - CYP plus arabic numeral (40% homology of amino acid sequence, eg. CYP1) Subfamily - 40-55% homology of amino acid sequence; eg. CYP1A Sub-Sub-family - additional arabic numeral when more than 1 subfamily has been identified; eg. CYP1A2 Italics indicate gene (CYP1A2); regular font for;;Human Drug Metabolizing CYPs Located in Extrahepatic Tissues;Participation of the CYP Enzymes in Metabolism of;Red indicates enzymes important in drug metabolism Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002;Non-CYP oxidations;Non CYP transformations;Phase II transformations;Glucuronidation;;Sulfation;;Acetylation;;History of Acetaminophen;Acetaminophen metabolism;Toxicity of acetaminophen;Additional Effects on Drug Metabolism;Pregnane X Receptor (PXR);Mechanism of class I nuclear receptor action;Pregnane X Receptor (PXR);Constitutive Androstane Receptor (CAR);PXR and CAR Protect Against Xenobiotics;;PXR and CAR ligands;;Acetaminophen toxicity mechanism;NAPQI toxicity linked to PXR activation G. Guo et al. 2004, Toxicol Sci 82(2):374-80;;思考题