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Drug Disposition > Clearance & Hepatic Elimination > Flashcards

Clearance & Hepatic Elimination Flashcards

1
Q

Where can excretion of drugs occur?

A

renally, hepatic (biliary excretion), pulmonary

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2
Q

Significance of clearance of drugs?

A

It is the primary pharmacokinetic parameter describing drug elimination

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3
Q

What is the concept of clearance?

A

parameter than relates the rate of drug elimination to its concentration

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4
Q

What is the definition of clearance?

A

The apparent volume of plasma (or blood, or plasma water) completely cleared of drug per unit of time

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5
Q

In what situation is clearance constant irrespective of dose?

A

If drug PK is linear

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6
Q

When may drug PK not be linear?

A

Situations where you get enzyme/transporter saturation

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7
Q

How can you describe clearance?

A

By organ (hepatic, renal, pulmonary) and by site of measurement (plasma, blood, plasma water)

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8
Q

Why does clearance vary between drugs?

A
  • inefficient extraction through the elimination organ - only a fraction removed
  • additivity of clearance
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9
Q

What assumption do you make when determining rate of elimination in an organ?

A

That there is a quick distribution equilibrium - all change in concentration when passing through the organ is due to elimination

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10
Q

What is the extraction ratio?

A

How much of the drug is removed from the blood when passing through an organ (value 0 - 1)

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11
Q

How does extraction ratio relate to fraction escaping metabolism?

A

1-E = F for the given organ

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12
Q

Examples of drugs with a low hepatic extraction ratio?

A

Diazepam, warfarin, tolbutamide, phenytoin

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13
Q

Examples of drugs with a medium hepatic extraction ratio?

A

Quinidine, codeine, cyclosporine

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14
Q

Examples of drugs with high hepatic extraction ratio?

A

Alprenolol, propranolol, verapamil, lidocaine

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15
Q

Typical blood flow to the liver?

A

1300-1500mL/min

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16
Q

Typical blood flow to the kidney?

A

1100mL/min

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17
Q

Typical cardiac output?

A

6000mL/min

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18
Q

What is additivity of clearance?

A

liver and kidney are both major organs of elimination, so occurs in both and has a combined overall clearance

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19
Q

What are the major routes of hepatic elimination?

A

Metabolism and biliary excretion

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20
Q

Why is the liver so highly perfused?

A

Dual blood supply - hepatic artery and portal vein

21
Q

What does the portal vein supply to the liver?

A

Brings venous blood from the GI tract

22
Q

What does the hepatic artery supply to the liver?

A

Carries oxygenated blood to the liver

23
Q

What are the different fates for a drug molecule relating to hepatocytes?

A
  • 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)
24
Q

What factors influence hepatic clearance?

A
  • Hepatic blood flow
  • Plasma protein binding
  • Enzyme activity
  • Disease status
  • Transporter activity - uptake or reflux
25
Q

What types of drugs have clearance that is largely influenced by hepatic blood flow?

A

Those with a high excretion fraction (>0.7)

26
Q

What types of drugs have clearance that is largely influenced by plasma protein binding?

A

Those with a low excretion fraction (<0.3)

27
Q

What can increase hepatic blood flow?

A

Bed rest, thyrotoxicosis, isoprenaline

28
Q

What can decrease hepatic blood flow?

A

Exercise, heart failure, propranolol

29
Q

What can increase plasma protein binding (lower fu)?

A

alpha1-acid glycoprotein - stress, cancer, arthritis, Crohns, myocardial infarction

albumin - myalgia

30
Q

What can decrease plasma protein binding (higher fu)?

A

alpha1-acid glycoprotein - neonates, nephrosis

albumin - heart failure, burns, pregnancy

31
Q

What can increase enzyme activity to increase clearance?

A

enzyme induction - rifampicin (many enzymes) smoking (CYP1A2)

32
Q

Relevance of CYP1A2 induction clinically?

A

clozapine is metabolised by Cyp1A2 so smoking increases metabolism - patients require higher dose. narrow therapeutic index

33
Q

Which emzyme does smoking induce?

A

CYP1A2

34
Q

What can reversibly decrease enzyme activity to reduce clearance?

A

Ketoconazole

35
Q

What can irreversibly decrease enzyme activity to reduce clearance?

A

mibefradil

36
Q

What other factors can influence emzyme activity and affect clearance?

A

Genetic polymorphism e.g. in CYP3A5 - affects metabolism of tacrolimus

disease e.g. liver cirrhosis

37
Q

General principles of liver cirrhosis?

A
  • 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
38
Q

Effects of liver cirrhosis on drug elimination?

A

reduced clearance usually, can be very significant

39
Q

Why can plasma protein binding of drugs change in liver cirrhosis?

A

impaired albumin synthesis - affect distribution and elimination

40
Q

What determines whether changes need to be made to the dosage regimen of a drug in cirrhotic patients?

A
  • relevance of hepatic elimination for the drug

- severity of the liver cirrhosis

41
Q

Role of uptake transporters in hepatic clearance?

A

active uptake of drugs intothe hepatocyte

  • via e.g. OATP1B1
  • often coupled with subsequent metabolism
42
Q

Role of efflux transporters in hepatic clearance?

A

Exretion of drug or conjugates into the bile

  • e.g. excretion of rosuvastatin by BCRP
  • biliary excretion of glucuronnide metabolites
43
Q

What can reduce efflux or uptake transporter action in hepatic clearance?

A

Genetic polymorphism or inhibition

44
Q

What are the mechanical and structural requirements for biliary excretion?

A
  • active facilitated transport (as it must be moved by transporters)
  • polar (e.g. glucuronide metabolites)
  • large mW >350
45
Q

Average bile flow rate?

A

0.5-0.8mL/min

46
Q

What is the enterohepatic circulation circuit?

A
  • 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
47
Q

Physiologial purpose of enterohepatic circulation?

A

Recycle bile salts

48
Q

Which drugs are susceptible to enterohepatic circulation?

A 
Rosuvastatin
Mycophenolic acid (via glucuronide)
49
Q

What impact does enterohepatic circulation have on plasma concentrations over time?

A

Can cause spikes/fluctuations in plasma conc as it is removed into the bile then reabsorbed from the intestine

Drug Disposition (11 decks)

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