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Dosimetry and Kinetics

Dosimetry and Kinetics. Oct 17 2007. Casarett and Doull, Chapter 7, pp. 225-237 Timbrell, Chapter 3, pp 48-61. Exposure. External exposure – ambient air, water Dose received by body Dose at target organ Dose at target tissue Dose at target molecule.

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Dosimetry and Kinetics

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  1. Dosimetry and Kinetics Oct 17 2007 Casarett and Doull, Chapter 7, pp. 225-237 Timbrell, Chapter 3, pp 48-61

  2. Exposure • External exposure – ambient air, water • Dose received by body • Dose at target organ • Dose at target tissue • Dose at target molecule

  3. Exposure – DoseHow are they related ?Can we measure them ?How can we describe the crucial steps so that we can estimate what we can’t measure?

  4. kin kout The single compartment(one compartment) model

  5. Kinetics of absorption • Absorption is generally a first-order process • Absorption constant = ka • Concentration inside the compartment = C • C/t = ka * D where D = external dose

  6. First-Order Processes • Follow exponential time course • Rate is concentration-dependent v = [A]/t = k[A] • Units of k are 1/time, e.g. h-1 • Unsaturated carrier-mediated processes • Unsaturated enzyme-mediated processes

  7. Kinetics of elimination • Elimination is also generally a first-order process • Removal rate constant k, the sum of all removal processes • C/t = -kC where C = concentration inside compartment • C = C0e-kt • Log10C = Log10C0 - kt/2.303

  8. Kinetics of Enzyme-catalyzed Reactions Michaelis-Menten Equation: v = Vmax * [S] Km + [S] First-order where Km >> [S] Zero-order where [S] >> Km

  9. Second-Order Processes • Follow exponential time course • Rate is dependent on concentration of two reactants v = [A]/t = k[A]*[B]

  10. First-order elimination Half-life, t1/2 Units: time t1/2 = 0.693/k

  11. One compartment system

  12. First-order decay of plasma concentration

  13. Total body burden • Integration of internal concentration over time • Area under the curve

  14. Area under the curve (AUC)

  15. A more complex time-course

  16. Peripheral compartment kin kout Central compartment The two-compartment model Tissues Plasma

  17. Peripheral compartment Rapid equilibrium Slow equilibrium kin Central compartment Deep depot kout The three-compartment model

  18. The four-compartment model Mamillary model Peripheral compartment kin Central compartment Deep depot Kidney kout

  19. A B C D The four-compartment model Catenary model kout kin

  20. Physiologically-Based Pharmacokinetic Modeling • Each relevant organ or tissue is a compartment • Material flows into compartment, partitionnns into and distributes around compartment, flows out of compartment – usually in blood • If blood flow rates, volume of compartment and partition coefficient are known, can write an equation for each compartment • Assuming conservation of mass, solve equations simultaneously – can calculate concentration (mass) in each compartment at any time

  21. Example of equation δkidney/δt = (Cak * Qa) – (Ck * Qvk) IN OUT Rate of change of the amount in the kidney = Concentration in (incoming) arterial blood X arterial blood flow Minus Concentration in (outgoing) venous blood X venous blood flow

  22. Example of a model Air inhaled Lungs Venous blood Arterial blood Rest of body Liver Metabolism Kidneys Urine

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