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43 Cards in this Set

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Elimination Mechanisms

Biotransformation - irreversible removal of drug by chemical conversion to metabolite




Excretion - irreversible removal of intact drug

What is clearance?

measure of the efficiency of mechanisms involved in drug removal from body


- determines steady state conc.

Systemic Clearance

Fraction of blood volume containing the drug that flows through the organ is eliminated of drug per unit time

Hepatic Clearance (ClH)

-biliary excretion


-liver


-biotransformation (Phase I and II enzymes)

Renal Clearance (ClR)

-kidneys


-glomerular filtration rate


-tubular absorption and excretion

Intrinsic clearance

measure of the intracellular removal of drug

Clearance in context with physiology

-difference between arterial [drug] and venous [drug] = due only to elimination processes b/c Qa = Qv

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)

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



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

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

What are the three ways to estimate ClR?

-excretion rate approach


-excretion interval approach


-cumulative excretion approach

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

Hepatic Clearance - Liver anatomy

Liver has two blood supplies - hepatic artery and portal vein


Metabolism:


Phase I - oxidation, reduction, hydrolysis


Phase II - conjugation

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

Phase II enzymes



-mediate conjugation of an endogenous molecule to a function group

What types of phase II enzymes are there?

UGT (UDP glucuronosyltransferases)


ST (sulfotransferases)


GST (Glucothione-s-transferases)
NAT (N-acetyltransferases)
MT (Methyltransferases)
Amino-acid conjugases

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



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

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

Effect of enzyme activity on hepatic clearance

-hepatocellular metabolic enzyme activity is rate-limiting


-ClH is directly proportional to enzyme activity



Michaelis-menten kinetics

Vmax is directly proportional to enzyme concentration (capacity term)




Km is inversely proportional to affinity between drug and enzyme (affinity term)

What is enzyme induction?

An increase in enzyme concentration which leads to an increase in enzyme function

Intrinsic Clearance

-Cl int changes with changes in physiological condition --> translate to changes in Cls and half-life




-not constant when Cu exceeds Km

Well-stirred model

-critical determinant of Css and dose regimen





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

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

What are factors that affect hepatic blood flow ?

Physiological - age, postural change, food, exercise




Pathophysiological - disease (CHF), drugs

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

Factors affecting the fraction unbound ?

-competitive interactions


-genetic factors


-capacity for binding --> disease



Renal Clearance

-kidney is primary organ of metabolite excretion


-eliminates polar drugs


-Tubular secretion and tubular reabsorption (active reabsorption requires proteins)

The nephron

basic anatomical and functional unit of the kidney


Components:


-glomerulus


-proximal tubule


-loop of Henle


-distal tubule


-collecting tubule

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

How to measure renal function?

Use creatinine because it is not bound to plasma proteins and only undergoes glomerular filtration

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

Intact Nehpron Hypothesis

Loss of either glomerular or tubular function means the loss of the whole nephron




-all-or-nothing

Active tubular secretion

-can be inferred when renal clearance exceeds the capacity of GFR (Clr > fu(b) x GFR)




-drug-drug interactions can occur

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

What are factors affecting Tubular reabsorption?

Urine Concentration


Urine Flow


Urine pH

Urine concentration

Water reabsorption results in a concentration of the drug in the filtrate that enhances the concentration gradient for passive reabsoprtion

Urine Flow

Only affects drugs that undergo extensive TR


--> higher flow = less TR

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

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