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Y3 Med drug disposition > Hepatic elimination > Flashcards

Hepatic elimination Flashcards

1
Q

What is the primary pharmacokinetic parameter describing drug elimination?

A

Clearance - relates rate of drug elimination to its plasma concentration

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2
Q

What does clearance equal?

A

CL (L/h) = Rate of elimination / C plasma

CL = (F dose)/AUC

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3
Q

What is clearance as a PK parameter?

A

CL is the apparent volume of plasma (or blood) completely cleared of drug per unit of time L/h or L/min

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4
Q

What does the value of clearance depend on?

A

Depends on the site of measurement

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5
Q

Does clearance depend on dose?

A

NO, clearance is CONSTANT irrespective of the dose, if the drug PK is linear.
If you change the dose, the clearance will not change - e.g. if you double the dose, concentration in plasma is doubled, rate of elimination is doubled, but clearance remains the same

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6
Q

When will clearance = flow rate?

A

When there is a perfect filter and all the volume is cleared

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7
Q

What can clearance never exceed?

A

Can never exceed the blood flow to that particular organ. (maximum clearance is blood flow)

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8
Q

What is the fractional rate of removal?

A

Elimination rate constant per unit of time.
k = rate of elimination / amount
k = CL/V

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9
Q

After 1 half life, how much of the dose is left?

A

50% (time taken for the plasma concentration to fall by half, once distribution equilibrium has been achieved

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10
Q

Would you expect 2 drugs with the same clearance value to have the same half life?

A
  • if volumes of distribution are different then NO

- if they are the same then YES (very rarely occurs)

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11
Q

How would you calculate half life on a graph?

A
  • Extrapolate lines on graph at half concentration

- half life = (ln2)/k = (0.693.V)/CL

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12
Q

What is half life influenced by?

A

It is a secondary parameter influenced by both distribution and elimination

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13
Q

What does the loading dose equal?

A

loading dose = V x Css

*Css = steady-state intervals

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14
Q

What does the maintenance dose equal?

A

F D/ = CL Css

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15
Q

Why do clearance values vary among the drugs?

A
  1. Inefficient extraction through the elimination organ (e.g. liver) - only a fraction removed passing through the organ
  2. Additivity of clearance - clearance may be a composite of the contribution of different organs
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16
Q

What does the rate of elimination equal?

A

Rate of elimination = Rate In - Rate Out

MASS BALANCE

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17
Q

What does the rate into the organ equal?

A

Rate in = delivery to organ - (product of blood flow Q x Arterial concentration A)

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18
Q

What does the rate out of the organ equal?

A

Rate out = Exit from organ - Blood flow x venous concentration

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19
Q

What is the entering concentration to an organ equal to?

A

Entering conc = conc in the arterial blood

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20
Q

What is the rate out of an organ when normalising to entering concentration?

A

Q(1-E)

E is the extraction ratio –> has to be blood clearance .

Clearance = (rate of elimination)/(entering concentration)
Clb = Q.E
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21
Q

What do the values of the extraction ratio mean?

A

E=0 No elimination

E=1 Complete elimination

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22
Q

What is the hepatic extraction ratio, and how do you work out the fraction escaping hepatic metabolism?

A

Eh

1-Eh = Fh

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23
Q

What is the typical blood flow value for the liver?

A

1300-1500 ml/min

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24
Q

What is the typical blood flow value for the kidney?

A

1100 ml/min

25
Q

What is the typical blood flow value for the cardiac output?

A

6000 ml/min

26
Q

How is the oral bioavailability described with an equation?

A

F = Fa.Fg.Fh

Fa - fraction absorbed
Fg - fraction escaping intestinal metabolism
Fh - fraction escaping hepatic metabolism

27
Q

What equation for oral bioavailability takes into account metabolism and biliary excretion?

A

F = Fa(1-Eg).(1-Eh)

Eg - metabolism
Eh - metabolism, biliary excretion

28
Q

What contributes to low bioavailability?

A

High hepatic and intestinal extraction (high Eh and Eg)

29
Q

When can clearance be additive?

A

(liver and kidney) when eliminating organs are arranged in parallel

Rate of elimination = rate of renal excretion + rate of hepatic metabolism

CL.C = CLr.C + CLh.C
(divide by plasma conc C)

CL = CLr + CLh

  • not applicable when organs are in series (liver-lungs)
30
Q

What are the 2 major routes of hepatic elimination?

A
  1. metabolism

2. biliary excretion

31
Q

What is the blood supply to the liver?

A

(highly perfused organ)

Dual blood supply:

  1. portal vein (1.1 L/min) - brings venous blood from the GI tract
  2. Hepatic artery (0.4 L/min)
32
Q

What can drug molecules bind to in hepatic blood flow?

A

Can either bind to the plasma proteins or blood cells.

Then moves into the hepatocyte via active transport

33
Q

What happens to the drug molecule when inside the hepatocyte?

A

It can be effluxed into the bile or the drug itself could be metabolised (by P450 and UGT enzymes). The metabolite then goes into systemic circulation

34
Q

What 5 factors influence hepatic clearance?

A
  1. Hepatic blood flow
  2. Plasma protein binding
  3. Enzyme activity
  4. Disease status
  5. Transporter activity - uptake or efflux
35
Q

What drugs does hepatic blood flow and hepatic clearance affect?

A

ONLY affects drugs with high Eh (hepatic extraction) (>0.7)

*rate limiting step is blood flow - can change hepatic clearance

36
Q

What drugs have a low hepatic extraction ratio (Eh <0.3)?

A

Molecules that are not very good substrates for enzymes or transporter - binding seems to be slower and more limited

37
Q

Does blood flow affect drugs with low hepatic extraction ratio?

A

Doesn’t really make a difference as other factors are even slower so not as sensitive to blood flow characteristics

38
Q

What drugs would be affected by conditions that change levels of albumin?

A

Only relevant for drugs with LOW hepatic extraction

*changing albumin levels can affect protein binding and hepatic clearance

39
Q

What are the 2 major plasma proteins?

A
  • alpha1-acid glycoprotein

- albumin

40
Q

What conditions is albumin low in and what affect does this have on fraction unbound drugs?

A

Albumin is low in heart failure, burns and pregnancy, so fraction unbound is much higher

41
Q

What conditions have low alpha1-acid glycoprotein and what does this lead to?

A

Neonate, nephrosis –> higher fraction unbound

42
Q

What enzyme induction influences hepatic clearance?

A

Smoking can induce some metabolic enzymes (CYP1A2), e.g. rifampicin and clozapine metabolised by enzymes : smokers have higher hepatic clearance so dosage needs to be adjusted

43
Q

What enzyme inhibition can influence hepatic clearance?

A

Reversible (e.g. ketoconazole) or irreversible (mibefradil, grapefruit juice), irreversible inhibition needs a new molecule to be synthesised

44
Q

What else can reduce hepatic clearance?

A
  • Genetic polymorphism (changes in CYP3A583*/3 with variant can have reduced clearance of tacrolimus etc)
  • liver cirrhosis
45
Q

What is liver cirrhosis caused by?

A

Commonly by excessive alcohol intake, hepatitis B and C

46
Q

What are the clinical implications of liver cirrhosis?

A
  • decreased liver volume and portal hypertension
  • generally reduced activity of metabolic enzymes
  • renal function (GFR) often impaired in patients with liver cirrhosis
  • generally irreversible, in advanced stages liver transplant is the only option
47
Q

What affect can liver cirrhosis have on albumin?

A

Impaired albumin synthesis leading to effects on the plasma protein binding of drugs and impacting on clearance

48
Q

What do modifications of dosage regimens in liver cirrhosis depend on?

A
  • relevance of hepatic elimination for a drug

- severity of liver cirrhosis (Child-Pugh A (mild) – C (severe)

49
Q

What role do uptake transporters have on hepatic clearance?

A

Molecules that are substrates for OATP1B1, once they are in the hepatocyte, they are subsequently metabolised by P450s or UGTs

50
Q

What role do efflux transporters have on hepatic clearance?

A

The drug is taken up by OATP1B1 and then excreted into the bile by BCRP or PgP (e.g. rosuvastatin)
–> biliary excretion og glucuronide metabolites

51
Q

What could happen with a reduction in transporter activity in hepatic clearance?

A

If we have a reduction in the transporter activity of either of these transporters – can be either because another drug administered causes inhibition of transporters (DDI) or may have a genetic polymorphism that is associated with a reduced activity so that could reduce the hepatic clearance of the molecule if it mediated by these transporters

52
Q

What requirements are there for biliary excretion?

A
  • active facilitated transport

- polar, MW > 350

53
Q

How do you calculate biliary clearance?

A

CLbile = (bile flow x drug conc in bile) / drug conc in plasma

54
Q

What is the normal bile flow value range?

A

0.5-0.8 ml/min, generally very low, so if there is a drug that concentrates into the bile, it will drive the biliary clearance to much higher values

55
Q

What is enterohepatic circulation?

A
  1. Drug gets into liver
  2. Is then excreted into the bile duct
  3. Then excreted into the small intestine where 2 possible different routes take place:
    • molecule is excreted with faces
    • OR drug goes back into circulation via the superior mesenteric vein, portal vein and back into the liver to go round again
56
Q

What drugs are common to enterohepatic circulation?

A
  • rosuvastatin, mycophenolic acid (via glucuronide)

also occurs with bile salts*

57
Q

Describe the enterohepatic circulation of mycophenolic acid?

A
  • .Mycophenolic acid gets metabolized by glucuronides in the liver
  • Glucuronides get excreted into bile (very polar good candidates
  • Moves into the small intestine where it gets exposed to enzyme beta-glucuronidase which will convert metabolite back into parent (glucuronide)
  • Parent gets brought back to liver for recirculation
58
Q

What is the impact of enterohepatic recirculation on plasma concentration - time profile?

A

Molecule stays in the body for longer

Y3 Med drug disposition (12 decks)

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