Clearance Principles

Front 1

Elimination Mechanisms

Back 1

Biotransformation - irreversible removal of drug by chemical conversion to metabolite

Excretion - irreversible removal of intact drug

Front 2

What is clearance?

Back 2

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

- determines steady state conc.

Front 3

Systemic Clearance

Back 3

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

Front 4

Hepatic Clearance (ClH)

Back 4

-biliary excretion

-liver

-biotransformation (Phase I and II enzymes)

Front 5

Renal Clearance (ClR)

Back 5

-kidneys

-glomerular filtration rate

-tubular absorption and excretion

Front 6

Intrinsic clearance

Back 6

measure of the intracellular removal of drug

Front 7

Clearance in context with physiology

Back 7

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

Front 8

Extraction Ration (E)

Back 8

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)

Front 9

What are the factors affecting extraction?

Back 9

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

Front 10

Extraction Ratio Values

Back 10

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

Front 11

What is/are the rate limiting step(s) for High E vs Low E drugs?

Back 11

High E - rate-limiting step is blood perfusion rate (Q)

Low E- rate-limiting step is extraction

Front 12

What are the three ways to estimate ClR?

Back 12

-excretion rate approach

-excretion interval approach

-cumulative excretion approach

Front 13

Sigma-Minus or ARE plot

Back 13

-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

Front 14

Hepatic Clearance - Liver anatomy

Back 14

Liver has two blood supplies - hepatic artery and portal vein

Metabolism:

Phase I - oxidation, reduction, hydrolysis

Phase II - conjugation

Front 15

Liver metabolism

Cytochrome P450

Back 15

- phase I

-uncover/add a functional group

CYP = sueprfamily

first arabic number = family

Capital letter = subfamily

second arabic number = specific isoenzyme

Front 16

Phase II enzymes

Back 16

-mediate conjugation of an endogenous molecule to a function group

Front 17

What types of phase II enzymes are there?

Back 17

UGT (UDP glucuronosyltransferases)

ST (sulfotransferases)

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

Front 18

PK consequences of genetic polymorphism

Back 18

-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

Front 19

What are the physiological determinants of hepatic clearance and that affect the Well-stirred model?

Back 19

-Hepatic blood flow (QH)

-Fraction unbound (Fu(b))

-Intrinsic clearance

Front 20

Effect of extraction ratio on hepatic clearance

Back 20

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

Front 21

Effect of enzyme activity on hepatic clearance

Back 21

-hepatocellular metabolic enzyme activity is rate-limiting

-ClH is directly proportional to enzyme activity

Front 22

Michaelis-menten kinetics

Back 22

Vmax is directly proportional to enzyme concentration (capacity term)

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

Front 23

What is enzyme induction?

Back 23

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

Front 24

Intrinsic Clearance

Back 24

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

-not constant when Cu exceeds Km

Front 25

Well-stirred model

Back 25

-critical determinant of Css and dose regimen

Front 26

Well-stirred model of Clh for IV administration

Back 26

- 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

Front 27

Well-stirred model for Clh for oral administration

Back 27

-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

Front 28

What are factors that affect hepatic blood flow ?

Back 28

Physiological - age, postural change, food, exercise

Pathophysiological - disease (CHF), drugs

Front 29

What are factors that affect intrinsic clearance?

Back 29

-enzyme induction --> incr. Cl int

-enzyme inhibition

-genetic polymorphism

-disease state - hepatic disease

-age

-nutritional status

-size of administered dose

Front 30

Factors affecting the fraction unbound ?

Back 30

-competitive interactions

-genetic factors

-capacity for binding --> disease

Front 31

Renal Clearance

Back 31

-kidney is primary organ of metabolite excretion

-eliminates polar drugs

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

Front 32

The nephron

Back 32

basic anatomical and functional unit of the kidney

Components:

-glomerulus

-proximal tubule

-loop of Henle

-distal tubule

-collecting tubule

Front 33

Glomerular filtation

Back 33

-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

Front 34

How to measure renal function?

Back 34

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

Front 35

Renal function impairment

Back 35

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

Front 36

Intact Nehpron Hypothesis

Back 36

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

-all-or-nothing

Front 37

Active tubular secretion

Back 37

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

-drug-drug interactions can occur

Front 38

Tubular Reabsorption

Back 38

- 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

Front 39

What are factors affecting Tubular reabsorption?

Back 39

Urine Concentration

Urine Flow

Urine pH

Front 40

Urine concentration

Back 40

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

Front 41

Urine Flow

Back 41

Only affects drugs that undergo extensive TR

--> higher flow = less TR

Front 42

Urine pH

Back 42

-apply pH partition hypothesis

-pH depends/affected by time of day,diet,drugs

-can alkalize or acidify to alter the unionized fraction --> enhancing TR

Front 43

Identidying the Clr mechanism

Back 43

- Cldrug/Cl inulin < 1 --> drug is partially reabsorbed

- Cldrug/Cl inulin = 1 --> drug is filtered only

- Cldrug/Cl inulin > 1 --> drug is actively secreted