Clearance III-IV- Hepatic+Renal

Clearance III-IV- Hepatic+Renal - Clearance III IV Hepatic...

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1 Clearance III – IV Hepatic and Renal
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2 Practice Problems From Book Drug Monograph 9 – Phenobarbital Questions 1-5 Don’t get hung up on e -kt Should understand the gist of the intro material
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3 HERD Q H Cl int E Cl H C pss,avg L/min L/min L/min mg/L 1.5 10 0.87 1.30 0.77 1.0 10 0.91 0.91 1.10 1.5 20 0.93 1.40 - 0.77 - LERD 1.5 0.01 0.0066 0.0099 101 1.0 0.01 0.0099 0.0099 101 - 1.5 0.2 0.013 0.0195 51
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4 Some Lessons LERD: Cl and blood levels won’t change much if liver perfusion changes will change if Cl int changes may need to increase dosage (notice that E doesn’t go hand in hand with Cl) HERD: Cl and blood levels will change if liver perfusion changes won’t change much if Cl int changes (and won’t need to change the dosage) (notice that E doesn’t go hand in hand with Cl)
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5 Liver and Oral Dosing F – bioavailability – F H – fraction that makes it through the liver hepatic availability (if 100% absorption F H = F total bioavailability ) • F H = 1-E HERD E ~1.0 – little bioavailability but a small change proportionately important e.g. 0.04 0.08 Not important if iv, im, sc dosing (before) but is potentially important if oral dosing
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6 Protein Binding Assume only unbound drug can get into liver cell and be cleared (there are exceptions) – Previously Cl int innate ability to clear but cant clear total drug only unbound SO multiply by fu • fu*Cl int,u same equations except fu incorporated
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7 Protein Binding E= fu*CL int,u / (Q H + fu*Cl int,u ) • CL H = Q H * fu*CL int,u / (Q H + fu*Cl int,u ) LERD – fu*CL int,u << Q H Then (by analogy to before)- – CL H = ~fu*CL int,u What about changes in binding?? low proteins in disease (e.g. uremia) something displaces the drug from it’s binding in both cases fu goes up
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8 An Example - LERD Cl int,u = 0.25 L/min, fu=0.1 Q H =1.5 • R 0 =0.25 mg/min E= 0.0164 Cl H = 1.5 l/min * 0.0164 = 0.0246 Don’t get confused – calculating total hepatic clearance (total drug) used fu to calculated fraction available inside liver
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9 Same Example -LERD • CL H = 0.0246 L/min Blood levels – C pss,avg = R 0 / Cl H =0.25 mg/min / 0.0246 L/min = 10.2 mg/L (this is total drug)
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10 What if fu changes LERD fu = 0.2 E= 0.0322 it’s gone up ~ 2 fold why? – amount unbound has gone up • Cl H = 1.5 l/min * 0.0322 = 0.0483 it’s gone up ~ 2 fold why? – amount unbound has gone up
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11 What if fu changes - LERD CL H = 0.0483 L/min Blood levels – C pss,avg = R 0 / Cl H =0.25 mg/min / 0.0483 L/min = 5.18 mg/L (this is total drug) (Clearance up, so drug conc down)
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12 WHAT about FREE DRUG Normal – C u = C
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