Hepatic Clearance Flashcards
What are the two mechanisms by which drugs can be eliminated by the liver?
- Biotransformation
- Billiary Excretion
What is the function of SLC transporters?
Influx transporters
What is the function of ABC transporters?
Efflux transporters
Where are Phase I enzymes most concentrated within the liver?
Closer to the central vein (Zone 3)
Where are Phase II enzymes most concentrated within the liver?
Closer to portal vein and arterial blood supply (Zone 1)
What are the physiological determinants of hepatic clearance?
- Hepatic blood flow (Qh)
- Unbound fraction (f(u)b)
- Intrinsic Clearance (Clint)
What aspects of hepatic does the Well-stired Model do a good job at representing?
- Shows interrelationship of the physiological determinants
- Allows qualitative predictions of how hepatic clearance changes with changes in physiological determinants
Review slide 6 for an equation of the Well-Stirred Model
What is the rate-limiting process for the hepatic clearance of high extraction ratio drugs?
Hepatic blood flow (Qh)
What factors impact hepatic blood flow?
- Disease (ex. heart failure)
- Physiological condtions (food=increased hepatic blood flow; exercise reduces hepatic blood flow)
What is the rate-limiting step for hepatic clearance in low extraction ratio drugs?
Factors that are not hepatic blood flow
ex. unbound fraction, intrinsic clearance
What factors impact unbound fraction? (affect low extraction ratio drugs)
Unbound fraction changes with:
- Altered affinity for binding
- Altered capacity of binding
What factors impact intrinsic clearance?
Intrinsic clearance changes with:
- Inhibition of enzymes (drug interaction, disease)
- Induction of enzymes (drug interaction, food/environmental chemical)
What physiological factors affect hepatic blood flow?
Age (older adults have reduction in hepatic blood flow)
Postural change (quick motion from lying down to upright can reduces cardiac output)
Food ingestion increases splanchic blood flow and hepatic blood flow
Exercise redistributes blood away from GI tract (lower hepatic blood flow)
What are some disease states that affect hepatic blood flow?
- Diseases that reduce cardac output (heart failure)
- Drugs (can increase or decrease cardiac output due to hemodynamic interactions)
- Intra- and extrahepatic shunting of blood
What is the effect of enzyme induction on hepatic clearance?
Enzyme induction increases intrinsic clearance, which in turn increases hepatic clearance
What is the effect of enzyme inhibition on hepatic clearance?
Enzyme inhibition reduces intrinsic clearance, which inturn decreases hepatic clearance
What factors affect intrinsic clearance?
- Enzyme induction (increase)
- Enzyme inhibition (decrease)
- Size of administered dose (concern in non-linear PK)
- Interindividual differences in metabolism
- Disease states
- Age (neonates and elderly have reduced enzyme activity)
- Nutritional status (deficiencies can reduce enzyme activity)
- Unbound fraction
Do drugs with high extraction ratios have high bioavailability?
No, high extraction ratio drugs have low bioavailability (they are metabolized at a greater rate)
Do drugs with low extraction ratios have high bioavailability?
Yes, low extraction ratio drugs have high bioavailability (drug is metabolized at lower rate, more reaches the tissues)
What is the effect of liver disease on unbound fraction?
The liver synthesizes albumin, a plasma protein that can bind to drugs
In liver disease, albumin production can be lower = increased unbound fraction
What is the effect of changes in intrinisic clearance to the hepatic clearance of high extraction ratio IV drugs?
No effect on hepatic clearance or half-life
What is the effect of changes in intrinsic clearance to the hepatic clearance of high extraction ratio oral drugs?
Significant changes in Fo, oral clearance, oral AUC
What is the effect of changes in instrinsic clearance to the hepatic clearance of low hepatic clearance of low extraction ratio IV drugs?
Significant changes in hepatic clearance and half-life
What is the effect of changes in intrinsic clearance to the hepatic clearance of low extraction ratio oral drugs?
Significant changes in oral clearance and oral AUC
