Drug Elimination

Question 1

What is clearance?

Answer 1

rate at which volume of plasma is cleared of substance per unit time

Question 2

What is the equation for clearance?

Answer 2

C = (elimination rate)/(plasma conc)

Question 3

Where are most drugs excreted?

Answer 3

kidney

Question 4

What are the three renal processes?

Answer 4

glomerular filtration, tubular secretion, passive tubular reabsorption

Question 5

What is filtered during glomerular filtration?

Answer 5

most molecules, the smaller and more positively charged, the better they filter
protein bound drugs aren’t filtered

Question 6

What is the equation for excretion?

Answer 6

excretion = GFR x normal plasma concentration

Question 7

What is filtered in tubular secretion?

Answer 7

ionized drugs are transported using SLC transporters

Question 8

What SLC transporters are involved in tubular secretion?

Answer 8

OCTs (cation transporters) and OATs (anion transporters), p-glycoprotein, MRP2 (conjugated metabolites)

Question 9

How do drug-drug interactions affect renal clearance?

Answer 9

1. if two drugs are competing for same transporter, their clearance could decrease
2. drugs could block the transporters for other drugs

Question 10

What happens during passive tubular reabsorption?

Answer 10

some lipid soluble drugs can be reabsorbed in distal tubule

Question 11

How does pH effect renal excretion?

Answer 11

lowering the pH (acidification) promotes excretion of weak bases
increasing the pH (alkalization) promotes excretion of weak acids

Question 12

What is a high extraction drug?

Answer 12

E > 0.7, “flow limited” as liver has extremely high capacity to metabolize them

Question 13

What is a low extraction drug?

Answer 13

E < 0.3, limited by hepatic capacity and fraction of free drug

Question 14

What are high extraction drugs sensitive to?

Answer 14

liver blood flow

Question 15

What are low extraction drugs sensitive to?

Answer 15

intrinsic hepatic metabolism and protein binding

Question 16

What is biliary duct excretion?

Answer 16

transfer of drug from plasma to bile through hepatocytes

Question 17

What transporters are used in biliary duct excretion?

Answer 17

many of the same ones used in the kidney (OATs and OCTs)

Question 18

How does genetic variation in transporters affect the treatment of high cholesterol?

Answer 18

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

Question 19

What is the enterohepatic cycle?

Answer 19

1. drugs glucoronidized in the liver and secreted into bile
2. in gut, can be cleaved by bacteria to reactivate drug
3. drug is reabsorbed

Question 20

What is the effect of the enterohepatic cycle?

Answer 20

increases the half life of the drug

Question 21

What is the effect of the antibiotics on oral contraceptives?

Answer 21

oral contraceptives undergo the enterohepatic cycle and antibiotics decrease gut bacteria so less contraceptives are recycled
makes it less effective