Clearance & Hepatic Elimination Flashcards
Where can excretion of drugs occur?
renally, hepatic (biliary excretion), pulmonary
Significance of clearance of drugs?
It is the primary pharmacokinetic parameter describing drug elimination
What is the concept of clearance?
parameter than relates the rate of drug elimination to its concentration
What is the definition of clearance?
The apparent volume of plasma (or blood, or plasma water) completely cleared of drug per unit of time
In what situation is clearance constant irrespective of dose?
If drug PK is linear
When may drug PK not be linear?
Situations where you get enzyme/transporter saturation
How can you describe clearance?
By organ (hepatic, renal, pulmonary) and by site of measurement (plasma, blood, plasma water)
Why does clearance vary between drugs?
- inefficient extraction through the elimination organ - only a fraction removed
- additivity of clearance
What assumption do you make when determining rate of elimination in an organ?
That there is a quick distribution equilibrium - all change in concentration when passing through the organ is due to elimination
What is the extraction ratio?
How much of the drug is removed from the blood when passing through an organ (value 0 - 1)
How does extraction ratio relate to fraction escaping metabolism?
1-E = F for the given organ
Examples of drugs with a low hepatic extraction ratio?
Diazepam, warfarin, tolbutamide, phenytoin
Examples of drugs with a medium hepatic extraction ratio?
Quinidine, codeine, cyclosporine
Examples of drugs with high hepatic extraction ratio?
Alprenolol, propranolol, verapamil, lidocaine
Typical blood flow to the liver?
1300-1500mL/min
Typical blood flow to the kidney?
1100mL/min
Typical cardiac output?
6000mL/min
What is additivity of clearance?
liver and kidney are both major organs of elimination, so occurs in both and has a combined overall clearance
What are the major routes of hepatic elimination?
Metabolism and biliary excretion
Why is the liver so highly perfused?
Dual blood supply - hepatic artery and portal vein
What does the portal vein supply to the liver?
Brings venous blood from the GI tract
What does the hepatic artery supply to the liver?
Carries oxygenated blood to the liver
What are the different fates for a drug molecule relating to hepatocytes?
- binding to blood cells or plasma proteins
- active transport into hepatocytes
- passive diffusion into or out of hepatocytes
- metabolism (once inside hepatocyte)
- biliary excretion (from hepatocyte)
What factors influence hepatic clearance?
- Hepatic blood flow
- Plasma protein binding
- Enzyme activity
- Disease status
- Transporter activity - uptake or reflux
What types of drugs have clearance that is largely influenced by hepatic blood flow?
Those with a high excretion fraction (>0.7)
What types of drugs have clearance that is largely influenced by plasma protein binding?
Those with a low excretion fraction (<0.3)
What can increase hepatic blood flow?
Bed rest, thyrotoxicosis, isoprenaline
What can decrease hepatic blood flow?
Exercise, heart failure, propranolol
What can increase plasma protein binding (lower fu)?
alpha1-acid glycoprotein - stress, cancer, arthritis, Crohns, myocardial infarction
albumin - myalgia
What can decrease plasma protein binding (higher fu)?
alpha1-acid glycoprotein - neonates, nephrosis
albumin - heart failure, burns, pregnancy
What can increase enzyme activity to increase clearance?
enzyme induction - rifampicin (many enzymes) smoking (CYP1A2)
Relevance of CYP1A2 induction clinically?
clozapine is metabolised by Cyp1A2 so smoking increases metabolism - patients require higher dose. narrow therapeutic index
Which emzyme does smoking induce?
CYP1A2
What can reversibly decrease enzyme activity to reduce clearance?
Ketoconazole
What can irreversibly decrease enzyme activity to reduce clearance?
mibefradil
What other factors can influence emzyme activity and affect clearance?
Genetic polymorphism e.g. in CYP3A5 - affects metabolism of tacrolimus
disease e.g. liver cirrhosis
General principles of liver cirrhosis?
- commonly caused by excessive alcohol, Heptatitis B and C
- decreased liver volume and portal hypertension
- generally reduced activity of metabolic enzymes (some enzymes affected more than others)
- GFR often impaired in cirrhotic patients
- generally irreversible and transplant is the only option once advanced
Effects of liver cirrhosis on drug elimination?
reduced clearance usually, can be very significant
Why can plasma protein binding of drugs change in liver cirrhosis?
impaired albumin synthesis - affect distribution and elimination
What determines whether changes need to be made to the dosage regimen of a drug in cirrhotic patients?
- relevance of hepatic elimination for the drug
- severity of the liver cirrhosis
Role of uptake transporters in hepatic clearance?
active uptake of drugs intothe hepatocyte
- via e.g. OATP1B1
- often coupled with subsequent metabolism
Role of efflux transporters in hepatic clearance?
Exretion of drug or conjugates into the bile
- e.g. excretion of rosuvastatin by BCRP
- biliary excretion of glucuronnide metabolites
What can reduce efflux or uptake transporter action in hepatic clearance?
Genetic polymorphism or inhibition
What are the mechanical and structural requirements for biliary excretion?
- active facilitated transport (as it must be moved by transporters)
- polar (e.g. glucuronide metabolites)
- large mW >350
Average bile flow rate?
0.5-0.8mL/min
What is the enterohepatic circulation circuit?
- eliminated from liver into the bile
- bile drains into small intestine (here it can be eliminated in faeces)
- can get absorbed again into the superior mesenteric vein which feeds hepatic vein, and back to the liver
Physiologial purpose of enterohepatic circulation?
Recycle bile salts
Which drugs are susceptible to enterohepatic circulation?
Rosuvastatin Mycophenolic acid (via glucuronide)
What impact does enterohepatic circulation have on plasma concentrations over time?
Can cause spikes/fluctuations in plasma conc as it is removed into the bile then reabsorbed from the intestine
