Hepatic clearance

Question 1

Influencing factors

Answer 1

Hepatic blood flow
Drug binding to plasma proteins or cell protein
membrane permeability
intrinsic clearance

Question 2

Intrinsic hepatic clearance is influenced by

Answer 2

affinity for metabolising enzymes or transporting systems which promote their secretion into bile

Question 3

> 0.7

Answer 3

• extensive first pass metabolism
• sensitive to changes in blood flow and less sensitive to changes in PPB or CLint
• extensive first pass metabolism

Question 4

0.7-0.3

Answer 4

• capacity limited
• sensitive to changes in intrinsic clearance
• no or little first pass effect

Question 5

< 0.3

Answer 5

• dependent on PPB/ cell protein binding

Question 6

Billary excretion of drugs

Answer 6

• drugs with MW > 500 are excreted in bile
• MW 300-500 excreted into both urine and bile
• <300 excreted exclusively into urine

Question 7

enterohepatic circulation

Answer 7

• once secreted into the intestine via the bile duct drug/metabolite may be readsorbed into blood circulation or excreted into the faeces

Question 8

In vitro test systems

Answer 8

• hepatocytes: all enzymes present; no cofactors required
• S9: contains microsomal and cytosolic enzymes; cofactors supplemented for incubations; P450 content lower than microsomes
• Microsomes: p450’s, FMO, UGT, requires cofactors for incubation

NB: UGT mediated degradation cannot be quantified

Question 9

Metabolites which are rehydrolysed into parent compound

Answer 9

Primary conjugative metabolites, glucuronides and sulfates

Question 10

Limits of well stirred model

Answer 10

Fu*Clint,u&raquo_space; Q =>
Hepatic clearance approaches Q

Fu*Clint,u &laquo_space;Q
Compound is metabolically stable