Pharmacokinetics 4: Drug Excretion

Question 1

What is drug excretion?

Answer 1

The process whereby an unchanged drug undergoes permanent removal from the body via kidneys or hepatobiliary system.

Question 2

How is drug elimination different to excretion?

Answer 2

Irreversible removal of the drug + drug lost through biotransformation

Question 3

Which organs are the main excretory organs? What other organs can be used for excretion?

Answer 3

The kidneys and the liver are the primary excreting organs.

Sweat and tears

Saliva (most is swallowed though)

Breast milk (basic lipophilic drugs)

Hairs, nails, skin minor overall

Question 4

What kinds of drugs can be excreted in breast milk?

Answer 4

Basic lipophilic drugs (eg cocaine)

Question 5

What are the main ways for drug to be removed?

Answer 5

Metabolism within the liver and gut wall is the primary route (>75% of drugs)

Renal clearance is less common but also a route (20%)

Bile excretion (4- 5%)

Question 6

Why are the kidneys such a large site of drug excretion?

Answer 6

They receive a large blood flow (1L/min which is 25% of CO at rest) 10% of this is filtered at the glomerulus.

Question 7

What percentage of drugs use the kidneys as their primary route of excretion?

Answer 7

25%

Question 8

Do kidneys remove the parent drug or the metabolite from the blood?

Answer 8

Both (Drugs that are excreted unchanged in urine are called renally cleared drugs)

Question 9

Examples of renally cleared drugs:

Answer 9

Penicillins

Digoxin

Cephalosporins

Antifungals

Metformin

Question 10

What drugs are filtered at the glomerulus?

Answer 10

Drugs that are unbound pass through glomerular pores.

Protein bound drugs are inhibited and stay in the blood.

Question 11

Which drugs are reabsorbed at the proximal tubule?

Answer 11

Mainly small, lipophilic, neutral drugs

Question 12

How can drugs move into and out of the kidneys?

Answer 12

Glomerular filtration (unbound drugs) Into filtrate

Passive reabsorption out of filtrate

Active transport Into filtrate

Drug excretion depends on these 3 factors.

Question 13

Where does active transport of drugs into urine take place?

Answer 13

In the proximal tubules

Question 14

What is GFR among adults?

Answer 14

~120ml/min [180L/day in adults]

Question 15

How does active transport from the blood into the filtrate take place?

Answer 15

They depend on both SLC and ABC drug transporters.

SLC transporters are located on basolateral membrane.

ABC transporters pump drugs from proximal tubule cells into the urinary lumen.

Question 16

True or False:

Amount of drug transported from blood to urine by transporters is constant.

Answer 16

True, however, theoretically these transporters can be saturated at higher drug doses.(only drug where this is known to happen is alcohol)

Question 17

What causes passive reabsorption of drugs back into the blood?

Answer 17

The drugs must be permeant for this to take place. For this reason only small, lipophilic and neutral or nonionised drugs can be reabsorbed.

Question 18

What determines how much reabsorption takes place?

Answer 18

Reabsorption is proportional to drug concentration in blood.

Drug pKa also matters (CLr may change with varying urine pH)

Question 19

What happens to proteins bound to plasma?

Answer 19

Only free drug is filtered (bound drug doesn’t)

Free and bound drugs are both actively transported into the urine.

Question 20

What influences urinary pH?

Answer 20

Diet (high protein diet = acidic urine)

Question 21

How does pH affect urinary excretion?

Answer 21

Acidic drugs are -ve in alkaline urine = less reabsorption.

Basic drugs in acidic pH = less reabsorption

Question 22

What is actual renal clearance?

Answer 22

It is indicated by parent drug concentrations in the urine.

Baseline renal clearance is shown by fu x GFR and secretion/reabsorption creates the actual renal clearance.

Question 23

When is a drug said to be undergoing active secretion?

Answer 23

if RC > fu x GFR

Question 24

When is a drug said to be undergoing active reabsorption?

Answer 24

if RC < fu x GFR

Question 25

How can active renal clearance be determined?

Answer 25

By administering blockers of active secretion pathways. (eg probenecid and cimetidine)

Question 26

What does probenecid do?

Answer 26

Blocks active secretion of organic anions. Thus it is used to prevent excretion of certain drugs such as penicillin.

Question 27

What does cimetidine do?

Answer 27

Blocks active secretion of organic cations.

Question 28

How are drugs excreted via hepato-biliary system?

Answer 28

Some drugs undergo direct hepato-biliary excretion. (Can supplement renal excretion or metabolims)

Many drugs form conjugates that are pumped into bile.

These drugs are pumped into bile via mostly SLC transporters in basolateral membranes and pumped into the bile via cannalicular membrane ABC transporters.

Question 29

What is a potential consequence to biliary excretion?

Answer 29

Drugs can be deconjugated in the GI tract (via commensal bacteria production fo beta - glucoronidase) and reabsorbed as parent drug which allows drug to be used for longer.

If lipophilic drug can undergo reabsorption from GI-tract back into the liver.

This process complicates the pharmacokinetics of some drugs (eg. morphine)

Question 30

What transporters are located on basolateral side of proximal tubules?

Answer 30

SLC transporters (OCT1, OAT2 etc)

Question 31

What transporters are located on luminal side of proximal tubules?

Answer 31

ABC transporters

Question 32

What transporters are located on basolateral membrane of hepatocytes?

Answer 32

SLC transporters

Question 33

What transporters are located on cannalicular membrane of bile duct?

Answer 33

ABC transporters

Question 34

What kind of cells do bile canalicular membranes have?

Answer 34

Polarized cells with distinct membranes with distinct patterns of cells.

Question 35

What influences which molecules are transported by canalicular transporters?

Answer 35

Molecular mass

Question 36

What kind of molecules do canalicular transporters prefer?

Answer 36

Large, polar molecules.

Question 37

What determines whether a compound is excreted via urine vs faeces?

Answer 37

How big the molecules is. Larger molecules are excreted via faeces (bile) and smaller molecules via urine.

Question 38

What happens to drug toxicity if bile ducts are blocked?

Answer 38

Due to inability to express via the biliary route, drugs that are normally excreted via that route become much more toxic.

Question 39

Formula for total body clearance:

Answer 39

CLtot = CLr + CLh + CLother

CLr refers to renally cleared drug (No metabolism)

CLh refers to hepatically cleared drug

CLother refers to other methods of drug clearance

Question 40

What measure indicates renal role in excretion?

Answer 40

fe (fraction of drug excreted unchanged)

High fe indicates high renal role in clearance and vice versa for low fe.

Question 41

How is clearance of a drug assessed?

Answer 41

Dose/AUC of dose-response curve

Question 42

What does clearance tell us?

Answer 42

Volume of blood cleared of drug per unit time. (i.e efficiency of elimination of a drug from the body)

Question 43

What is drug clearance important for?

Answer 43

Determining the level of drugs in plasma at steady state. (when rate of drug administration = rate of drug elimination)