Hepatic elimination Flashcards
What is the primary pharmacokinetic parameter describing drug elimination?
Clearance - relates rate of drug elimination to its plasma concentration
What does clearance equal?
CL (L/h) = Rate of elimination / C plasma
CL = (F dose)/AUC
What is clearance as a PK parameter?
CL is the apparent volume of plasma (or blood) completely cleared of drug per unit of time L/h or L/min
What does the value of clearance depend on?
Depends on the site of measurement
Does clearance depend on dose?
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
When will clearance = flow rate?
When there is a perfect filter and all the volume is cleared
What can clearance never exceed?
Can never exceed the blood flow to that particular organ. (maximum clearance is blood flow)
What is the fractional rate of removal?
Elimination rate constant per unit of time.
k = rate of elimination / amount
k = CL/V
After 1 half life, how much of the dose is left?
50% (time taken for the plasma concentration to fall by half, once distribution equilibrium has been achieved
Would you expect 2 drugs with the same clearance value to have the same half life?
- if volumes of distribution are different then NO
- if they are the same then YES (very rarely occurs)
How would you calculate half life on a graph?
- Extrapolate lines on graph at half concentration
- half life = (ln2)/k = (0.693.V)/CL
What is half life influenced by?
It is a secondary parameter influenced by both distribution and elimination
What does the loading dose equal?
loading dose = V x Css
*Css = steady-state intervals
What does the maintenance dose equal?
F D/ = CL Css
Why do clearance values vary among the drugs?
- Inefficient extraction through the elimination organ (e.g. liver) - only a fraction removed passing through the organ
- Additivity of clearance - clearance may be a composite of the contribution of different organs
What does the rate of elimination equal?
Rate of elimination = Rate In - Rate Out
MASS BALANCE
What does the rate into the organ equal?
Rate in = delivery to organ - (product of blood flow Q x Arterial concentration A)
What does the rate out of the organ equal?
Rate out = Exit from organ - Blood flow x venous concentration
What is the entering concentration to an organ equal to?
Entering conc = conc in the arterial blood
What is the rate out of an organ when normalising to entering concentration?
Q(1-E)
E is the extraction ratio –> has to be blood clearance .
Clearance = (rate of elimination)/(entering concentration) Clb = Q.E
What do the values of the extraction ratio mean?
E=0 No elimination
E=1 Complete elimination
What is the hepatic extraction ratio, and how do you work out the fraction escaping hepatic metabolism?
Eh
1-Eh = Fh
What is the typical blood flow value for the liver?
1300-1500 ml/min
What is the typical blood flow value for the kidney?
1100 ml/min
What is the typical blood flow value for the cardiac output?
6000 ml/min
How is the oral bioavailability described with an equation?
F = Fa.Fg.Fh
Fa - fraction absorbed
Fg - fraction escaping intestinal metabolism
Fh - fraction escaping hepatic metabolism
What equation for oral bioavailability takes into account metabolism and biliary excretion?
F = Fa(1-Eg).(1-Eh)
Eg - metabolism
Eh - metabolism, biliary excretion
What contributes to low bioavailability?
High hepatic and intestinal extraction (high Eh and Eg)
When can clearance be additive?
(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)
What are the 2 major routes of hepatic elimination?
- metabolism
2. biliary excretion
What is the blood supply to the liver?
(highly perfused organ)
Dual blood supply:
- portal vein (1.1 L/min) - brings venous blood from the GI tract
- Hepatic artery (0.4 L/min)
What can drug molecules bind to in hepatic blood flow?
Can either bind to the plasma proteins or blood cells.
Then moves into the hepatocyte via active transport
What happens to the drug molecule when inside the hepatocyte?
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
What 5 factors influence hepatic clearance?
- Hepatic blood flow
- Plasma protein binding
- Enzyme activity
- Disease status
- Transporter activity - uptake or efflux
What drugs does hepatic blood flow and hepatic clearance affect?
ONLY affects drugs with high Eh (hepatic extraction) (>0.7)
*rate limiting step is blood flow - can change hepatic clearance
What drugs have a low hepatic extraction ratio (Eh <0.3)?
Molecules that are not very good substrates for enzymes or transporter - binding seems to be slower and more limited
Does blood flow affect drugs with low hepatic extraction ratio?
Doesn’t really make a difference as other factors are even slower so not as sensitive to blood flow characteristics
What drugs would be affected by conditions that change levels of albumin?
Only relevant for drugs with LOW hepatic extraction
*changing albumin levels can affect protein binding and hepatic clearance
What are the 2 major plasma proteins?
- alpha1-acid glycoprotein
- albumin
What conditions is albumin low in and what affect does this have on fraction unbound drugs?
Albumin is low in heart failure, burns and pregnancy, so fraction unbound is much higher
What conditions have low alpha1-acid glycoprotein and what does this lead to?
Neonate, nephrosis –> higher fraction unbound
What enzyme induction influences hepatic clearance?
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
What enzyme inhibition can influence hepatic clearance?
Reversible (e.g. ketoconazole) or irreversible (mibefradil, grapefruit juice), irreversible inhibition needs a new molecule to be synthesised
What else can reduce hepatic clearance?
- Genetic polymorphism (changes in CYP3A583*/3 with variant can have reduced clearance of tacrolimus etc)
- liver cirrhosis
What is liver cirrhosis caused by?
Commonly by excessive alcohol intake, hepatitis B and C
What are the clinical implications of liver cirrhosis?
- 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
What affect can liver cirrhosis have on albumin?
Impaired albumin synthesis leading to effects on the plasma protein binding of drugs and impacting on clearance
What do modifications of dosage regimens in liver cirrhosis depend on?
- relevance of hepatic elimination for a drug
- severity of liver cirrhosis (Child-Pugh A (mild) – C (severe)
What role do uptake transporters have on hepatic clearance?
Molecules that are substrates for OATP1B1, once they are in the hepatocyte, they are subsequently metabolised by P450s or UGTs
What role do efflux transporters have on hepatic clearance?
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
What could happen with a reduction in transporter activity in hepatic clearance?
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
What requirements are there for biliary excretion?
- active facilitated transport
- polar, MW > 350
How do you calculate biliary clearance?
CLbile = (bile flow x drug conc in bile) / drug conc in plasma
What is the normal bile flow value range?
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
What is enterohepatic circulation?
- Drug gets into liver
- Is then excreted into the bile duct
- 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
What drugs are common to enterohepatic circulation?
- rosuvastatin, mycophenolic acid (via glucuronide)
also occurs with bile salts*
Describe the enterohepatic circulation of mycophenolic acid?
- .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
What is the impact of enterohepatic recirculation on plasma concentration - time profile?
Molecule stays in the body for longer
