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43 Cards in this Set
- Front
- Back
Elimination Mechanisms |
Biotransformation - irreversible removal of drug by chemical conversion to metabolite Excretion - irreversible removal of intact drug |
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What is clearance? |
measure of the efficiency of mechanisms involved in drug removal from body - determines steady state conc. |
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Systemic Clearance |
Fraction of blood volume containing the drug that flows through the organ is eliminated of drug per unit time |
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Hepatic Clearance (ClH) |
-biliary excretion -liver -biotransformation (Phase I and II enzymes) |
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Renal Clearance (ClR) |
-kidneys -glomerular filtration rate -tubular absorption and excretion |
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Intrinsic clearance |
measure of the intracellular removal of drug |
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Clearance in context with physiology |
-difference between arterial [drug] and venous [drug] = due only to elimination processes b/c Qa = Qv |
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Extraction Ration (E) |
fraction of drug entering the eliminating organ that is removed during transit through the organ (i.e. E = 0.25, organ removes all drug in 0.25 L of incoming blood each minute if Q = 1 L/min) |
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What are the factors affecting extraction? |
a. Drug binding to blood cells b. Drug binding to plasma proteins c. Unbound drug diffusion into the hepatocyte d. Unbound drug excretion into bile e. Unbound drug enzymatic biotransformation f. Blood perfusion rate (Q) to the liver - factors affecting low E drugs |
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Extraction Ratio Values |
High E drug (non-restricted clearance) when E > 0.7 Intermediate E when 0.3 < E < 0.7 Low E drug (restricted clearance) when E < 0.3 |
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What is/are the rate limiting step(s) for High E vs Low E drugs? |
High E - rate-limiting step is blood perfusion rate (Q)
Low E- rate-limiting step is extraction |
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What are the three ways to estimate ClR? |
-excretion rate approach -excretion interval approach -cumulative excretion approach |
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Sigma-Minus or ARE plot |
-overcomes problem of fluctuation -requires measurement of total parent drug excreted into the urine -cumulative amount excreted at time t, summing at each time interval |
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Hepatic Clearance - Liver anatomy |
Liver has two blood supplies - hepatic artery and portal vein Metabolism: Phase I - oxidation, reduction, hydrolysis Phase II - conjugation |
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Liver metabolism Cytochrome P450 |
- phase I -uncover/add a functional group CYP = sueprfamily first arabic number = family Capital letter = subfamily second arabic number = specific isoenzyme |
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Phase II enzymes |
-mediate conjugation of an endogenous molecule to a function group |
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What types of phase II enzymes are there? |
UGT (UDP glucuronosyltransferases) ST (sulfotransferases) GST (Glucothione-s-transferases) |
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PK consequences of genetic polymorphism |
-poor metabolizers and extensive metabolizers -reduction in Cls , incr. Css and t1/2 --> potential toxicity -altered metabolite profiles -altered drug-drug interactions -altered first-pass/therapeutic effects |
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What are the physiological determinants of hepatic clearance and that affect the Well-stirred model? |
-Hepatic blood flow (QH) -Fraction unbound (Fu(b)) -Intrinsic clearance |
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Effect of extraction ratio on hepatic clearance |
High E drug (Eh > 0.7) - Qh is the rate-limiting step Low E drug (Eh < 0.3) - fraction unbound/enzyme activity/Cl int are rate limiting Intermediate E (0.3 < E < 0.7 -depends on relative rate of blood flow |
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Effect of enzyme activity on hepatic clearance |
-hepatocellular metabolic enzyme activity is rate-limiting -ClH is directly proportional to enzyme activity |
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Michaelis-menten kinetics |
Vmax is directly proportional to enzyme concentration (capacity term) Km is inversely proportional to affinity between drug and enzyme (affinity term) |
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What is enzyme induction? |
An increase in enzyme concentration which leads to an increase in enzyme function |
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Intrinsic Clearance |
-Cl int changes with changes in physiological condition --> translate to changes in Cls and half-life -not constant when Cu exceeds Km |
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Well-stirred model |
-critical determinant of Css and dose regimen |
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Well-stirred model of Clh for IV administration |
- Cl is dependent on Qh , rate limiting process Qh << Fu(b) + Cl int -fu(b) and Clint --> rate limiting for low E enzyme induction will incr. Cl int and this incr. hepatic clearance (Cl int = Vmax/Km) drug-drug interaction --> competition --> decr affinity --> higher Km --> lower Clint |
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Well-stirred model for Clh for oral administration |
-increasing Qh increases F b/c it reduces its residence time in the liver -Increases in Clint or fu(b) decrease F b/c it means the liver is more efficient in removing the drug -Low E drugs --> F is independent of all factor |
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What are factors that affect hepatic blood flow ? |
Physiological - age, postural change, food, exercise Pathophysiological - disease (CHF), drugs |
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What are factors that affect intrinsic clearance? |
-enzyme induction --> incr. Cl int -enzyme inhibition -genetic polymorphism -disease state - hepatic disease -age -nutritional status -size of administered dose |
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Factors affecting the fraction unbound ? |
-competitive interactions -genetic factors -capacity for binding --> disease |
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Renal Clearance |
-kidney is primary organ of metabolite excretion -eliminates polar drugs -Tubular secretion and tubular reabsorption (active reabsorption requires proteins) |
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The nephron |
basic anatomical and functional unit of the kidney Components: -glomerulus -proximal tubule -loop of Henle -distal tubule -collecting tubule |
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Glomerular filtation |
-GFR is 120 ml/min only 10 % of CO -function of unbound drug in plasma Clr = fu(b) x GFR - if GF is the only Clr mechanism , then Er is low Er = rate of extraction / rate of presentation |
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How to measure renal function? |
Use creatinine because it is not bound to plasma proteins and only undergoes glomerular filtration |
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Renal function impairment |
Clr varies directly with creatine clearance, then Cls is proportional to renal function only if drug is excreted unchanged and not affected if the drug is eliminated by metabolism |
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Intact Nehpron Hypothesis |
Loss of either glomerular or tubular function means the loss of the whole nephron -all-or-nothing |
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Active tubular secretion |
-can be inferred when renal clearance exceeds the capacity of GFR (Clr > fu(b) x GFR) -drug-drug interactions can occur |
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Tubular Reabsorption |
- 180 L of protein free glomerular filtrate is formed each date, only 1.5 L is excreted -active/passive reabsorption infer passive reabsorption when Clr is less than Cl by filtration, Clr < fu(b) x GFR |
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What are factors affecting Tubular reabsorption? |
Urine Concentration Urine Flow Urine pH |
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Urine concentration |
Water reabsorption results in a concentration of the drug in the filtrate that enhances the concentration gradient for passive reabsoprtion |
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Urine Flow |
Only affects drugs that undergo extensive TR --> higher flow = less TR |
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Urine pH |
-apply pH partition hypothesis -pH depends/affected by time of day,diet,drugs -can alkalize or acidify to alter the unionized fraction --> enhancing TR |
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Identidying the Clr mechanism |
- Cldrug/Cl inulin < 1 --> drug is partially reabsorbed - Cldrug/Cl inulin = 1 --> drug is filtered only - Cldrug/Cl inulin > 1 --> drug is actively secreted |