lect 6 Distribution

lect 6 Distribution - NS120/220-Molecular Toxicology...

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NS120/220 -Molecular Toxicology Xenobiotic Xenobiotic Distribution Distribution and Storage and Storage
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Learning Objectives 1. What is meant by distribution of a xenobiotic? Describe how chemicals are distributed through the body. 2. What is Volume of Distribution? What is the relationship between Vd and plasma concentration? 3. What are the characteristics of the major xenobiotic binding proteins in plasma? 4. Where are xenobiotics stored in the body? 5. How does protein binding a ect toxicity? 6. Give examples of how xenobiotics bind to Albumin. How could you determine which site a xenobiotic bound? 7. Explain how albumin is used in medical procedures to treat jaundice or Wilson’s disease.
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Readings: Practical Aspects of the Ligand-binding and Enzymatic Properties of Human Serum Albumin, Kragh-Hansen et al. Biol. Pharm. Bull. 25(6) p. 695-704 (2000) http://www.sis.nlm.nih.gov/ToxTutor/Tox2/ a31.htm
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Chemical Exposure Free Free Plasma Plasma Chemical Chemical Site of Action Plasma Protein- “Bound” Chemical Storage in Tissues (fat) Excretion METABOLISM METABOLISM Absorption
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I. GENERAL PRINCIPLES Distribution: The reversible transfer of xenobiotics from one location in the body to another A. Extent of Distribution Determined by: partitioning across various membranes binding to tissue components binding to blood components (RBC, plasma protein) physiological volumes
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Components of Total Body Water Vascular 3 L 4% BW Extravascular 9 L 13% BW Extracellular Intracellular 28 L 41% BW
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Distribution Distribution : Blood carries the agent to and from its site Blood carries the agent to and from its site of action, storage depots, organs of of action, storage depots, organs of transformation, and organs of elimination transformation, and organs of elimination Rate of distribution (rapid) dependent Rate of distribution (rapid) dependent upon upon blood flow characteristics of toxicant (affinity for characteristics of toxicant (affinity for the tissue, and the partition coefficient) Distribution may change over time Distribution may change over time
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Distribution: Storage and Binding Storage in Adipose tissue--Very lipophilic compounds (DDT) will store in fat. Rapid mobilization of the fat (starvation) can rapidly increase blood concentration Storage in Bone--Chemicals analogous to Calcium--Fluoride, Lead, Strontium Binding to Plasma proteins--can displace endogenous compounds. Only free is available for adverse effects or excretion
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Absorption of Lipophilic Xenobiotics:
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