Drug Elimination Flashcards
What is clearance?
rate at which volume of plasma is cleared of substance per unit time
What is the equation for clearance?
C = (elimination rate)/(plasma conc)
Where are most drugs excreted?
kidney
What are the three renal processes?
glomerular filtration, tubular secretion, passive tubular reabsorption
What is filtered during glomerular filtration?
most molecules, the smaller and more positively charged, the better they filter
protein bound drugs aren’t filtered
What is the equation for excretion?
excretion = GFR x normal plasma concentration
What is filtered in tubular secretion?
ionized drugs are transported using SLC transporters
What SLC transporters are involved in tubular secretion?
OCTs (cation transporters) and OATs (anion transporters), p-glycoprotein, MRP2 (conjugated metabolites)
How do drug-drug interactions affect renal clearance?
- if two drugs are competing for same transporter, their clearance could decrease
- drugs could block the transporters for other drugs
What happens during passive tubular reabsorption?
some lipid soluble drugs can be reabsorbed in distal tubule
How does pH effect renal excretion?
lowering the pH (acidification) promotes excretion of weak bases
increasing the pH (alkalization) promotes excretion of weak acids
What is a high extraction drug?
E > 0.7, “flow limited” as liver has extremely high capacity to metabolize them
What is a low extraction drug?
E < 0.3, limited by hepatic capacity and fraction of free drug
What are high extraction drugs sensitive to?
liver blood flow
What are low extraction drugs sensitive to?
intrinsic hepatic metabolism and protein binding
What is biliary duct excretion?
transfer of drug from plasma to bile through hepatocytes
What transporters are used in biliary duct excretion?
many of the same ones used in the kidney (OATs and OCTs)
How does genetic variation in transporters affect the treatment of high cholesterol?
if you have a variation of OATP1B1 that is impaired, statins cannot be taken up by hepatocytes
statin treatment doesn’t work and there is statin myotoxicity
What is the enterohepatic cycle?
- drugs glucoronidized in the liver and secreted into bile
- in gut, can be cleaved by bacteria to reactivate drug
- drug is reabsorbed
What is the effect of the enterohepatic cycle?
increases the half life of the drug
What is the effect of the antibiotics on oral contraceptives?
oral contraceptives undergo the enterohepatic cycle and antibiotics decrease gut bacteria so less contraceptives are recycled
makes it less effective
