l19_pks_cont

l19_pks_cont - 20.201 Lect#19 Page 1 20.201 Mechanisms of...

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20. 201 Lect #1 9 11/2/05 Page 1 Lecture #1 9 : PBPK November 2, 2005 20. 201 Mechanisms of Drug Action
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Review of Lecture #18 • Began covering simple compartment models of PKs • Discussed zero- and first-order kinetics in terms of implications for drug behavior in the body • Derived rate expressions for 1- and 2-compartment models • Began to develop the idea of stringing together one- compartment models into more complicated systems
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20. 201 Lect #1 9 11/2/05 Page 3 Pharmacokinetic Behavior Two compartments with I.V. injection ~ Injected drug distributes in blood “instantaneously” ~ Drug moves out of blood into tissue compartment: first-order (why?) ~ As blood concentration falls, higher tissue concentration drives return to blood (why?) ~ Examine plasma concentration versus time plot in this model Blood k el injection d [ D ] p dt = k 21 [ D ] tis k 12 [ D ] p k el [ D ] p Integrate [ D ] p t = Ae α t + Be β t Tissue k 21 k 12 ln([D] t ) Time Rapid first-order distribution First-order elimination + = k 12 + k 21 + k el = k 21 k el A = [D] p 0 k 21 B = [D] p 0 k 21 ln([D] t ) Time Blood Tissue
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20. 201 Lect #1 9 11/2/05 Page 4 Route of Administration Blood/Plasma Absorption Tissues Distribution Route of Elimination Routes of administration (1) Enteral - • oral • sublingual •rec ta l (2) Parenteral - • intravenous (iv) • intramuscular (im) • subcutaneous (sc) (3) Other - • inhalation •top ica l • transdermal Pharmacokinetics: Basic Concepts
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20. 201 Lect #1 9 11/2/05 Page 5 PBPK Models: Pro's and Con's • Two types of PK models: ~ Simple models : - one and two compartments - no physiological meaning to the compartments or the rate constants - Example: rate constant for elimination from blood (k el ) has many contributions, including diffusion into tissues, excretion, metabolism ~ Physiological models : - compartments represent biologically/physiologically real organs, tissues, excretion routes, etc. - rate constants represent real biological processes, such as rate of metabolism • PBPK models are developed to provide predictive tools for drug development and, more importantly, for risk assessment ~ PBPK's predict distribution to individual tissues and targets ~ PBPK models adapt to changes in physiological or health status; example: alterations in metabolism in liver disease ~ PBPK models typically involve scaling from rodents to humans • Disadvantages: ~ Huge amounts of data required, which means many experiments to define each parameter ~ Impractical for pharmacologically relevant data such as blood half-life, etc.
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20. 201 Lect #1 9 11/2/05 Page 6 Cisplatin History • Cisplatin is one the most widely used anticancer drugs on the market • Clinically active against testicular, ovarian, lung and head/neck tumors • Usually given in combination with other anticancer drugs • Discovered by Barnett Rosenberg in the Dept. of Biophysics at Michigan State University • Rosenberg was studying the growth of E. coli in electrical fields and observed bizarre, filamentous growth of the bacteria
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This note was uploaded on 11/11/2011 for the course BIO 2.797j taught by Professor Matthewlang during the Fall '06 term at MIT.

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l19_pks_cont - 20.201 Lect#19 Page 1 20.201 Mechanisms of...

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