Classical+to+PBPK

Classical+to+PBPK - Classical to PBPK to Classical...

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Classical to PBPK to Classical
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Classical PK Aim – to predict plasma drug levels Presumption – Cp reflective of drug concentration at target KISS to the extreme Five fundamental constants F, ka, V D , Cl R , Cl H
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GI Tract Feces Bile LIVER P L A S M A LUNG NOSE MUSCLE FAT Kidney Urine Inter- Intra- stitial cellular 15% 40% 5% Total=60% BW (includes liver, lung etc) ..................... ..................... ....................... ................................ Absorption Excretion Distribution
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Biopharm to Bioavailability Routes of exposure Membrane transport Absorption Ficks Law Flux = P*A (Cout-Cin) Ion trapping Facilitated diffusion BIOAVAILABILITY Fraction (percentage) of drug that reaches the systemic blood
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A Start at Quantitation BIOAVAILABILITY Fraction (percentage) of drug that reaches the systemic blood Absorbed Absorbed Drug = F*S*Dose Administration Rate R A = Dose *F*S/tau Based on amount in systemic blood
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Cp, V D, Loading Dose C p =Dose/V d Useful but not real LD oral = C p * V d / (F*S) Loading dose
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Extrapolate Back to Zero Time 0 10 20 30 40 50 60 Cp (Plasma Drug Concentration) 20 50 80 200 500 800 10 100 1000 Cp,0=1000
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Clearance Eggs in a beaker What is it – Theoretical volume that is totally cleared of drug per unit time C ss,avg = R A / Cl T MD =Dose = [Cl *C pss, avg *tau]/S*F t ½ = ln2*V D /Cl A lot of unspoken assumptions in this!
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10 Hepatic Clearance Cl H = Q H * E E= fu*CL int,u / (Q H + fu*Cl int,u ) LERD vs HERD If E>fu*Q (Note – Cl int,u = Vmax/Km doesn’t hold at saturation)
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Renal Drug Handling Glomerulus Proximal Distal Urine Tubule Tubule X X X X X X X X Active Secretion Active or Passive Reabsorption Filtration Rate of Excretion= + Rate of glomerular filtration + Rate of tubular secretion - Rate of tubular reabsorption
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This note was uploaded on 08/26/2010 for the course PHRM 231 taught by Professor N/a during the Fall '07 term at UConn.

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Classical+to+PBPK - Classical to PBPK to Classical...

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