Metabolism of XenobioticsSlide 2Why?Slide 4Slide 5Phase I – Phase IIIdentification/quantitation of metabolitesSystems studiedOverview: Uptake and distribution (ADME)Passage across membranesSlide 11Metabolism of XenobioticsI. General OverviewAug 25, 2011L.M. BallRosenau [email protected]/TOXC 442 Fall 2011•Metabolism:Chemical reactions carried out by and in living systems–Breakdown of organic matter (eg food) to release energy (catabolism)–Construction of cell components (eg carbohydrates, proteins, lipids, nucleic acids, other macromolecules) using energy (anabolism)–Carried out by enzymes (+ co-factors)–Essential to life–No metabolism = no life•XenobioticSubstance foreign (xenos = foreign) to life (bios)Chemical found in a living system which is not “naturally” present in that organism.–Drugs (Drug metabolism)–Environmental pollutants–Not produced by organism–Not useful to organism–Metabolism carried out by enzymes (+ co-factors)–Metabolism serves to eliminate xenobiotics–Fundamental to toxicologyWhy?•Importance in Pharmacology/Therapeutics•Importance in Toxicology•Importance in Environmental Protection•Need to consider properties (therapeutic and/or toxic) of metabolites as well as those of the parent compound•Need to know –What metabolites are formed–Where they are formed–Kinetics of formation–Kinetics of eliminationInternational Society for Study of Xenobiotics (ISSX) www.issx.orgXenobioticaDrug Metabolism and Disposition (ASPET)Chemical Research in Toxicology (ACS)Drug Metabolism Reviews (ISSX)Current Drug MetabolismDrug Metabolism LettersPhase I – Phase II•Phase I: Chemical modifications that introduce or uncover functional groups on a xenobiotic that provide sites for Phase II metabolism•Phase II: Synthetic reaction of a xenobiotic (or of a Phase I metabolite of a xenobiotic) with an endogenous substance that results in introduction of polar, ionizable groups to enhance water solubility and hence excretionOHooOHHOOHCOOHOHBenzene PhenolIdentification/quantitation of metabolites•Extraction from biological matrix•Separation/purification•Analytical techniques•Chromatography–Thin-layer, gas, liquid, high-pressure liquid…. •Spectrometry–Mass, nuclear magnetic resonance, UV-vis, fluorescence•Radiolabelled parent compoundSystems studied•Whole animals (humans, rats)•Isolated perfused organs•Reconstructed organs/tissues•Cells (primary isolates, cultures) •Subcellular fractions–S9–Microsomes–Cytosol•Purified enzymes•Cells engineered to over/under express specific enzymes•Organisms with genes for specific enzymes knocked outOverview: Uptake and distribution(ADME)•Major Portals of Entry–Lung–Intestinal Tract–Skin•Major Sites of Metabolism–Liver–Lung–Intestinal Tract–Kidneys–Skin•Target organs•Major Routes of Elimination–Urine–Feces–Exhaled air–Pharmacokinetic descriptorsPassage across membranes•Passive diffusion (Fick’s Law)–Flux is proportional to concentration gradientJ = -D * ΔC/Δx•Transporters (can go against concentration gradient)•Metabolism generates a concentration
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