clearance and hepatic elimination

Question 1

what is metabolised?

Answer 1

 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

Question 2

what is excretion?

Answer 2

 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

Question 3

what is proportionality constant?

Answer 3

CLEARANCE is the parameter that relates rate of drug elimination to its plasma concentration:
CL = Rate of Elimination / C plasma

units = L/hr

Question 4

what is clearance as PK parameter/

Answer 4

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

Question 5

what is clearance?

Answer 5

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.

Question 6

what can blood clearance never exceed”

Answer 6

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.

Question 7

what is the elimination rate constant?

Answer 7

k = rate of elimination divided by amount

cl=k x v

Question 8

what is the half life?

Answer 8

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%.

Question 9

would you expect two drugs with the same clearance to have the same half life?

Answer 9

• 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.

Question 10

which PK parameters are relevatn for dosage regimen design/

Answer 10

Loading dose = V Css
Maintenance dose = F D/ = CL Css
 - dosing interval
Css – steady-state concentrations

Question 11

why do clearance level varys amoung drugs?

Answer 11

1. 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
2. Additivity of clearance
   - Clearance may be composite of the contribution of different organs

Question 12

what are examples of drugs with low extraction <0.3

Answer 12

• diazepam
• warfarin
• tolbutamide
• phenytoin

Question 13

what are examples are drugs with medium extraction 0.3-0.7/

Answer 13

• quinidine
• codeine
• cyclosporin

Question 14

what are examples of high extraction >0.7?

Answer 14

• alprenolol
• propranolol
• verapamil
• lidocaine

Question 15

what are the typical blood flow values?

Answer 15

liver = 1300-1500ml/min
kidney = 1100 ml/min
cardiac ouput = 6000ml/min

Question 16

what it total clearance?

Answer 16

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

Question 17

what are the major routes of hepatic metabolism?

Answer 17

1. metabolism
2. 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

Question 18

what are major cells in liver?

Answer 18

hepatocytes

Question 19

what is the summary of the clearance process?

Answer 19

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.

Question 20

what factors influence hepatic clearance?

Answer 20

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

Question 21

which drugs will be impacted by change to blood flow?

Answer 21

high Eh ( more than 0.7)

Question 22

what does low hepatic extraction cause?

Answer 22

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.

Question 23

what is the impact of plasma protein binding?

Answer 23

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

Question 24

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

Answer 24

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

Question 25

what factors influence hepatic clearance/

Answer 25

* increase Enzyme induction – rifampicin, smoking (CYP1A2, clozapine) * decrease Enzyme inhibition – reversible (e.g., ketoconazole) or irreversible (e.g., mibefradil) * decreaseGenetic polymorphism - CYP3A5*3/*3 (tacrolimus) * Liver cirrhosis

Question 26

what is liver cirrhosis?

Answer 26

 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

Question 27

what is the impact of liver cirrhosis on drug elimination?

Answer 27

 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.)

Question 28

what is the role of uptake and efflux transporters in hepatic clearance?

Answer 28

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

Question 29

what is billiary excretion?

Answer 29

1. Mechanism and structural requirements a. Active facilitated transport b. Polar; MW > 350 2. Biliary clearance

Question 30

what is the equation for billiary excretion?

Answer 30

= bile flow x drug conc in bile divided drug conc in plasma

Question 31

what should bile flow be?

Answer 31

0.5-0.8ml/min

Question 32

what is enterohepatic circulation?

Answer 32

 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

Question 33

what is the impact of enterohepatic recirculation on plasma concentration time profile/

Answer 33

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

Question 34

what factors influence hepatic clearance?

Answer 34

1. hepatic blood flow - affects drugs with high EH 2. Plasma protein binding – affects drugs with low EH e.g., decrease albumin in pregnancy - results in increase fu 3. Enzyme activity – inhibition or induction increase - Enzyme induction decrease - Enzyme inhibition decrease - Genetic polymorphism of some metabolic enzymes 4. Liver cirrhosis CL is generally decreased 5. Transporter activity decrease - Inhibition of uptake transporters or genetic polymorphism (OATP1B1)