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Kinetics, Modeling. Oct 15, 2006. Casarett and Doull, 6 th Edn, Chapter 7, pp. 225-237 7 th Edn, Chapter 7, pp. 305-317 Timbrell, Chapter 3, pp 48-61 (3 rd Edn). Exposure. External exposure – ambient air, water Dose received by body Dose at target organ Dose at target tissue - PowerPoint PPT Presentation
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Kinetics, Modeling
Oct 15, 2006
Casarett and Doull, 6th Edn, Chapter 7, pp. 225-2377th Edn, Chapter 7, pp. 305-317
Timbrell, Chapter 3, pp 48-61 (3rd Edn)
Exposure
• External exposure – ambient air, water
• Dose received by body
• Dose at target organ
• Dose at target tissue
• Dose at target molecule
• Molecular dose
• Repair
Exposure – Dose
How are they related ?Can we measure them ?
How can we describe the crucial steps so that we can
estimate what we can’t measure?
Enzymes: Biological catalysts
• Proteins• May have metals at active site• Act on “substrate”• May use/require co-factors
Kinetics of Enzyme-catalyzed Reactions
Michaelis-Menten Equation:
v = Vmax * [S]
Km + [S]
First-order where Km >> [S]
Zero-order where [S] >> Km
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
Second-Order Processes
• Follow exponential time course
• Rate is dependent on concentration of two reactants
v = [A]/t = k[A]*[B]
Uptake
Higher concentration
Lower concentration
Diffusion
Filtration
Pore
Lipid bilayer
Carrier
Facilitated diffusion
Active transpor
t
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
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
Volume of Distribution
Apparent volume in which a chemical is distributed in the body
Calculated from plasma concentration and dose:
Vd = Dose/C0
Physiological fluid space: approximately 1L/kg
The three-compartment model
Deepdepot
Peripheralcompartment
kin
kout
Centralcompartment
Slow equilibrium
Rapid equilibrium
The four-compartment model
Mamillary model
Deepdepot
Peripheralcompartment
kin
kout
Centralcompartment
Kidney
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
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
Example of a modelAir inhaled
Lungs
Arterial blood
Venous blood
Urine
Metabolism
Liver
Kidneys
Rest of body