Hepatic Clearance

Question 1

What is hepatic clearance?

Answer 1

direct quantitative measure of ability of liver to eliminate drugs

Question 2

What is the primary organ of drug biotransformation? How does drug reach this organ?

Answer 2

the liver
two blood supplies:
-arterial (25%)
-portal vein (75%)

Question 3

What are the physiological determinants of hepatic clearance?

Answer 3

hepatic blood flow (Qh)
unbound fraction (fu(b))
intrinsic clearance (Clint)

Question 4

What is the conceptual model for hepatic clearance?

Answer 4

the Well-Stirred model
Clh=Qh x fu(b) x Clint/Qh + fu(b) x Clint

Question 5

What does the Well-Stirred model allow for?

Answer 5

allows qualitative predictions of how Clh changes with changes in physiological determinants
-shows interrelationship of physiological determinants

Question 6

What is the typical value for hepatic blood flow?

Answer 6

1.5L/min

Question 7

What are some factors that can cause changes in Qh?

Answer 7

disease (ex: CHF–>decreased CO)
physiological conditions (ex: food increases Qh, exercise decreases Qh)

Question 8

Differentiate between high Eh and low Eh drugs in the context of Qh.

Answer 8

high Eh drug (Eh>0.7)
-Qh is rate-limiting to overall Clh
-as Eh approaches 1, changes in Qh will produce similar changes in Clh
low Eh drugs (Eh<0.3)
-Qh is not rate-limiting
-changes in Qh has limited affect on Clh

Question 9

What can cause changes in the fu(b)?

Answer 9

altered affinity for binding
altered capacity of binding

Question 10

Differentiate between high Eh and low Eh drugs in the context of fu(b).

Answer 10

high Eh drugs (Eh>0.7)
-fu(b) is not rate-limiting to Clh
-changes in fu(b) cause limited changes in Clh
low Eh drugs (Eh<0.3)
-fu(b) is rate-limiting to Clh
-changes in fu(b) result in proportional changes in Eh and Clh

Question 11

What is Clint?

Answer 11

measure of the intracellular removal of drug (transport and metabolic processes)

Question 12

What can cause changes in Clint?

Answer 12

inhibition (drug interaction, disease)
induction (drug interaction, food/environmental chemical)

Question 13

Differentiate between high Eh and low Eh drugs in the context of Clint.

Answer 13

high Eh drugs (>0.7)
-Clint is not rate-limiting to Clh
-changes in Clint cause limited changes in Clh
low Eh drugs (<0.3)
-Clint is rate-limiting to Clh
-changes in Clint result in proportional changes in Eh and Clh

Question 14

What are factors that affect Qh value?

Answer 14

physiological factors
-age (elderly have reduction in Qh)
-postural changes (supine to upright) decrease CO
-food ingestion increases splanchnic blood flow and increases Qh
-exercise redistributes blood away from GIT to decrease Qh
pathophysiological factors
-diseases that reduce CO
-drug (increase/decrease CO due to hemodynamic interactions)
-intra/extrahepatic shunting of blood (cirrhosis)

Question 15

What are factors that affect Clint value?

Answer 15

metabolic drug interactions
-induction (increases Clint)
–>increase in amount of enzyme, depends on dose+duration
-inhibition (decreases Clint)
–>reversible/non-reversible
-size of administered dose
–>high dose may cause saturation (non-linear PK)
interindividual differences in metabolism
-genetic or environmental
disease state
-hepatic disease=hard to predict, hyperthyroid=increased Clint
age
-neonate (reduced enzyme activity)
-elderly (reduced liver mass and enzyme concentration)
nutritional status
-protein & vitamin deficiency=decrease enzyme activity

Question 16

What are factors that affect fu(b) value?

Answer 16

affinity
-competitive interactions (endogenous, exogenous)
-genetic
capacity
-disease (inflammation, hypoalbuminemia)

Question 17

Why is the the Well-Stirred model valuable?

Answer 17

helps predict changes in Clh from changes in fu(b), Clint, and Qh
changes to Clh will impact Cls and thus must modify MD
MD=Css,ave x Cls/S x F

Question 18

What does oral clearance depend upon?

Answer 18

Clo = fu(b) x Clint
-depends only on unbound fraction and maximum enzyme capacity
-true for both high Eh and low Eh drugs
Clo is not the same as Cls

Question 19

Using the Well-Stirred model, describe Cls for intravenous administration for a high Eh drug and a low Eh drug.

Answer 19

high Eh drug:
-Clh=Qh
-for high Eh drug given IV, Qh determines Cls
low Eh drug:
-Clh=fu(b) x Clint
-for low Eh drug given IV, fu(b) and Clint determine Cls

Question 20

Using the Well-Stirred model, describe Fh for oral administration for a high Eh and a low Eh drug.

Answer 20

high Eh drug:
-Fh=Qh/fu(b) x Clint
-if Qh increases, then Fh increases (less residence time)
-if Clint or fu(b) increase, then Fh decrease
low Eh drug:
-Fh=Qh/Qh=1
-Fh is independent of all factors
-essentially carries most of drug throughout liver

Question 21

Describe the impact of changes in Clint on t1/2 for high Eh and low Eh drugs given by intravenous administration.

Answer 21

high Eh drug:
-no effect on Clh and t1/2
-t1/2=0.693 x Vd/Qh
low Eh drug:
-significant changes in Clh and t1/2
-t1/2=0.693 x Vd/fu(b) x Clint

Question 22

Describe the impact of changes in Clint on AUCo for high Eh and low Eh drugs given by oral administration.

Answer 22

high Eh drug:
-significant changes in AUCo
-AUCo=dose/Clo (Clo=fu(b) x Clint)
low Eh drug:
-significant changes in AUCo
-AUCo=dose/Clo (Clo=fu(b) x Clint)

Question 23

Describe the effect of changes in the fu(b) on Cls, F, and Vd for high Eh and low Eh drugs.

Answer 23

high Eh drugs:
-Clh=Qh (Cls insensitive to changes in fu(b))
-Fh=Qh/fu(b) x Clint (inversely proportional)
-Vd=Vb + Vt x fu(b)/fu(t)
low Eh drugs:
-Clh=fu(b) x Clint (limiting factor in Cls)
-Fh=Qh/Qh=1 (no factor)
-Vd=Vb + Vt x fu(b)/fu(t)

Question 24

Describe the effect of changes in fu(b) on t1/2 for high Eh and low Eh drugs.

Answer 24

high Eh drugs:
-t1/2=0.693 x (Vb + Vt x fu(b)/fu(t))/Qh
-fu(b) influences t1/2
low Eh drugs:
-t1/2=0.693 x (Vb + Vt x fu(b)/fu(t))/fu(b) x Clint
-fu(b) may have no influence on t1/2

Question 25

Describe the effect of changes in the fu(b) on AUC for high Eh and low Eh drugs following intravenous administration.

Answer 25

AUC=doseiv/Cls
for high Eh drugs:
-AUC=doseiv/Qh
for low Eh drugs:
-AUC=doseiv/fu(b) x Clint

Question 26

Describe the effect of changes in the fu(b) on AUC for high Eh and low Eh drugs following oral administration.

Answer 26

AUCo=F x doseo/Cls
for both high Eh and low Eh drugs:
-AUCo=doseo/fu(b) x Clint

Question 27

Describe the effect of changes in fu(b) on Css,total and Css,unbound for high Eh and low Eh drugs given by intravenous administration.

Answer 27

Css=Ko/Cls
Css,unbound=fu(b) x Css,total
high Eh drugs:
-Css,total=Ko/Qh
-Css,unbound=fu(b) x Ko/Qh
low Eh drugs:
-Css,total=Ko/fu(b) x Clint
-Css,unbound=Ko/Clint

Question 28

Describe the effect of changes in fu(b) on Css,total an Css,unbound for high Eh and low Eh drugs given by oral administration.

Answer 28

Css,ave=F x dose/t/Cls
Css,unbound=fu(b) x Css,total
for both high Eh and low Eh drugs:
-Css,ave=dose/t/fu(b) x Clint
-Css,unbound=dose/t/Clint
changes in fu(b) do not influence Css,unbound unless drug is high Eh given IV