clearance and hepatic elimination Flashcards
what is metabolised?
Chemical conversion where you end up with the metabolite which is usually polar – this means it can be excreted more easily
Major sites are liver and intestine
Is still a dominant mechanism of drug elimination (may be coupled with transporters)
Involves enzymatic conversion of a drug to metabolites
Metabolites are more polar and hydrophilic than the parent drug and are renally excreted
what is excretion?
Elimination of unchanged drug or its metabolites from the body
Occurs mostly in the kidney
Occurs also at other sites
Liver (biliary excretion)
Lungs (pulmonary)
This could be of the unchanged products or the metabolites
what is proportionality constant?
CLEARANCE is the parameter that relates rate of drug elimination to its plasma concentration:
CL = Rate of Elimination / C plasma
units = L/hr
what is clearance as PK parameter/
CL is the apparent volume of plasma (or blood) completely cleared of drug per unit of time L/h or L/min
Value of clearance depends on the site of measurement
Clearance is CONSTANT irrespective of the dose, if the drug PK is LINEAR. If you change the dose, clearance won’t change unless there are abnormalities in the drug
E.g. if you double the dose, conc in plasma is doubled, rate of elimination is double -clearnace stays the same
Plasma is the most common fluids for transport – could use blood or water in blood also.
Cannot mix the measurements – but it doesn’t matter which measurement you take
what is clearance?
Depending on which organ is contributing to elimination you can refer to what type of clearance is being carried out.
Depending on type of fluid you use you can also be more specific about what this is.
If it is not specified and just say clearance you can just assume it is plasma clearance as it is the most common.
Some of the newer molecules can undergo biliary clearance.
If you say renal clearance – usually means of the unchanged drug but you cannot assume this as sometimes metabolism does occur here so it could be the clearance of metabolites.
what can blood clearance never exceed”
Blood clearance can never exceed the blood flow to that organ. If the organ is the perfect filter then maximum clearance is the blood flow to that organ as it cannot be bigger then this. This is the limit – one important aspect to understand.
what is the elimination rate constant?
k = rate of elimination divided by amount
cl=k x v
what is the half life?
t1/2 - time taken for the plasma concentration to fall by half, once distribution equilibrium has been achieved.
One half life reduces the dose in the body by 50%, so two half lives would be the dose in the body is 25%.
would you expect two drugs with the same clearance to have the same half life?
- No, they have different volume distrubtion – but if this volumes are the same then yes it would be.
- You need the Vd of the two drugs to be the same.
which PK parameters are relevatn for dosage regimen design/
Loading dose = V Css
Maintenance dose = F D/ = CL Css
- dosing interval
Css – steady-state concentrations
why do clearance level varys amoung drugs?
- Inefficient extraction through the elimination organ (e.g., liver)
- only a fraction removed passing through the organ
- Q= blood flow
- Ca = flow in to organ
- Cv= flow out of the organ
- The difference between what is going in and what is going out should align with the rate of elimination via that particular organ - Additivity of clearance
- Clearance may be composite of the contribution of different organs
what are examples of drugs with low extraction <0.3
- diazepam
- warfarin
- tolbutamide
- phenytoin
what are examples are drugs with medium extraction 0.3-0.7/
- quinidine
- codeine
- cyclosporin
what are examples of high extraction >0.7?
- alprenolol
- propranolol
- verapamil
- lidocaine
what are the typical blood flow values?
liver = 1300-1500ml/min
kidney = 1100 ml/min
cardiac ouput = 6000ml/min
what it total clearance?
Total clearance is a sum of the renal and the hepatic
From here you can assess what the contribution is from each indivudal organ = certain drugs will have more dominant routes, which you can investigate and see what the consequences would be depending how and where there are cleared
what are the major routes of hepatic metabolism?
- metabolism
- biliary excretion
high perfused organ with a dual blood supply
Portal vein (1.1 L/min) – brings venous blood from the GI tract
Hepatic artery (0.4 L/min) - carries oxygenated blood to the liver
what are major cells in liver?
hepatocytes
what is the summary of the clearance process?
Molecule can either vind to the protein or it can bind to blood cells
The unbound molecule will go to the hepatocytes (passive diffusion, active transport (polar molecules rely on this uptake into heptatocyte)). Once in heptaticycte it can be effluxed into bile or the drug itself could be metabolised, to produce a metabolite which can then enter systemic circulation.
what factors influence hepatic clearance?
- Hepatic blood flow
- Plasma protein binding
- Enzyme activity
- Disease status
- Transporter activity – uptake or efflux
which drugs will be impacted by change to blood flow?
high Eh ( more than 0.7)
what does low hepatic extraction cause?
These type of molecules these parameters will have a role in the elimiation. Blood flow won’t have as much as a effect as these type of molecules are more heavily affected by the other molecules.
what is the impact of plasma protein binding?
Important for low EH drugs (<0.3)
fu 1-acid glycoprotein albumin
stress, cancer myalgia
arthritis, Crohn, myocardial infarction
fu neonate, nephrosis heart failure, burns, pregnancy
Only relevant if molecule falls into catergory of low Eh drugs.
If person is taking a drug that falls into this category you may see a change in the amount of elimination
An investigational new drug is eliminated entirely by hepatic metabolism, with a clearance of 1L/h in a healthy subjects (average Qh, in healthy subjects is 80L/h)
What is the expected clearance of this drug in a congestive heart failure patient with a Qh of 66L/h?
a) 0.66L/h
b) Unchanged compared with healthy
c) 66L/h
d) None of the above
b
Molecule has low extraction as clearance is much lower compared to hepatic blood flow. Moelcules with low extraction are not changed by change in blood flow, therefore we can assume there will be no major changes to that of a healthy patient
what factors influence hepatic clearance/
- increase Enzyme induction – rifampicin, smoking (CYP1A2, clozapine)
- decrease Enzyme inhibition – reversible (e.g., ketoconazole) or irreversible (e.g., mibefradil)
- decreaseGenetic polymorphism - CYP3A53/3 (tacrolimus)
- Liver cirrhosis
what is liver cirrhosis?
Commonly caused by excessive alcohol intake, Hepatitis B and C
Decreased liver volume in liver cirrhosis and portal hypertension
Generally reduced activity of metabolic enzymes – not all enzymes will be reduced to the same extent, but general trend
Renal function (GFR) often impaired in patients with liver cirrhosis
Generally irreversible, in advanced stages liver transplant is the only option – mostly need to prevent getting to this stage
what is the impact of liver cirrhosis on drug elimination?
Hepatic clearance of many drugs significantly reduced in liver cirrhosis!
Plasma protein binding of drugs may change (impaired albumin synthesis)
Modifications of the dosage regimens depends on
Relevance of hepatic elimination for a drug
Severity of liver cirrhosis (child-pugh, A-C) (a is the most mild, c is the most severe where the factors are more pronounced.)
what is the role of uptake and efflux transporters in hepatic clearance?
A. Active uptake of drugs into the hepatocyte (e.g., via OATP1B1)*
- often coupled with subsequent
metabolism
B. Efflux - excretion of drug or drug conjugates into the bile
- e.g. excretion of rosuvastatin by BCRP
- biliary excretion of glucuronide metabolites
decrease
Transporter activity - may be due to a DDI, inhibition or genetic polymorphism* MAY AFFECT HEPATIC CLEARANCE
what is billiary excretion?
- Mechanism and structural requirements
a. Active facilitated transport
b. Polar; MW > 350 - Biliary clearance
what is the equation for billiary excretion?
= bile flow x drug conc in bile
divided
drug conc in plasma
what should bile flow be?
0.5-0.8ml/min
what is enterohepatic circulation?
Occurs with bile salts
Apparent ALSO with certain drugs – e.g. rosuvastatin, mycophenolic acid (via glucuronide)
Once drug is in small intestine a small portion won’t get to faeces, it will go back to the liver.
This is a common mechanism of action for bile salts – but some of the drugs also follow the same pathway
Can be unchanged molecule or the metabolite.
Possibility of a small fraction of this to be eliminated and the rest will be circulated
what is the impact of enterohepatic recirculation on plasma concentration time profile/
Increase due to absorption, reach max dose which will decline over time but with other increases due to recirculation and it being present in body for longer which you need to take into account when looking at doses
what factors influence hepatic clearance?
- hepatic blood flow - affects drugs with high EH
- Plasma protein binding – affects drugs with low EH
e.g., decrease albumin in pregnancy - results in increase fu - Enzyme activity – inhibition or induction
increase - Enzyme induction
decrease - Enzyme inhibition
decrease - Genetic polymorphism of some metabolic enzymes - Liver cirrhosis
CL is generally decreased - Transporter activity
decrease - Inhibition of uptake transporters or genetic polymorphism (OATP1B1)
