Clearance and hepatic elimination Flashcards
What is elimination?
irreversible removal or loss of a drug from the body
What is metabolism?
- 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)
What is the primary pharmacokinetic parameter describing drug elimination?
Clearance
Concept of clearance:
CLEARANCE is the parameter that relates rate of drug elimination to its plasma concentration:
CL = Rate of Elimination / C plasma
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
Rate of elimination =
CL·C = CLb·Cb = CLu·Cu plasma* blood plasma water
- Value of clearance depends on the site of measurement
- Clearance is CONSTANT irrespective of the dose, if the drug PK is LINEAR
Description of clearance.
By Organ:
Hepatic –> CLH
Renal –> CL
Pulmonary –> CLpulm
Description of clearance.
By Site of Measurement:
Plasma–> CL
Blood –> CLb
Plasma water (unbound) –> CLu
Elimination rate constant:
k (min-1), defined as fractional rate of drug loss:
k = Rate of elimination/amount = CL x c / V x c = CL/v
CL = K x v
What is t1/2?
t1/2 - time taken for the plasma concentration to fall by half, once distribution equilibrium has been achieved
t1/2 = ln2/K
PK parameters relevant for dosage regimen design:
Loading dose = V Css
Maintenance dose
F D/t = CL Css
t - dosing interval
Css – steady-state concentrations
Why do CL 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
Extraction ratio:
CLb = Q x E
E 0–> 1
EH – hepatic extraction ratio
1- EH = FH - Fraction escaping hepatic metabolism
Typical blood flow values:
Liver - 1300-1500 ml/min
Kidney - 1100 ml/min
Cardiac output - 6000ml/min
First-pass metabolism:
- Loss of a drug as it passes through intestine and liver during absorption (presystemic metabolism)
F = Fa FG FH
= Fa (1- EG) (1- EH)
Fa – fraction absorbed
FG – fraction escaping intestinal metabolism
FH - fraction escaping hepatic metabolism
Clearance may be a composite of the contribution of different organs:
- Clearance can be additive – liver and kidney
–> when eliminating organs are arranged in parallel
Not applicable when organs are in series (liver – lungs)
CL x C = CLR x C + CLH x C
Hepatic elimination and liver blood supply:
Major routes of hepatic elimination:
- Metabolism
- Biliary excretion
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) - carries oxygenated blood to the liver
Factors influencing hepatic clearance:
- Hepatic blood flow
- Plasma protein binding
- Enzyme activity
- Disease status
- Transporter activity – uptake or efflux
Hepatic blood flow and hepatic clearance:
Affects only drugs with high EH (>0.7)
- Increase QH - bed rest, thyrotoxicosis, isoprenaline
- Decreased QH – exercise, heart failure, propranolol
Factors influencing hepatic clearance:
- Enzyme activity (CLint)
- Increased Enzyme induction –> rifampicin, smoking (clozapine)
- Decreased enzyme inhibition –> reversible (e.g., ketoconazole) or irreversible (e.g., mibefradil)
- Decreased genetic 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
- Renal function (GFR) often impaired in patients with liver cirrhosis
- Generally irreversible, in advanced stages liver transplant is the only option
Impact of liver cirrhosis on drug elimination:
- Hepatic clearance of many drugs significantly reduced in liver cirrhosis!
- Plasma protein binding of drugs may change
- Modifications of the dosage regimens depends on
- Relevance of hepatic elimination for a drug
- Severity of liver cirrhosis
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
- Decreased transporter activity - inhibition or genetic polymorphism*
Biliary excretion:
- Mechanism and structural requirements
a. Active facilitated transport
b. Polar; MW > 350 - Biliary clearance
CLbile = bile flow x drug conc in bile/ Drug conc in plasma
Enterohepatic circulation:
Liver –> Common bile duct –> Small intestine –> Superior mesenteric vein –> Portal vein –> Liver
Factors influencing hepatic clearance – summary
- Hepatic blood flow – affects drugs with high EH
- Plasma protein binding – affects drugs with low EH
e. g., decreased albumin in pregnancy - results in increased fu - Enzyme activity – inhibition or induction
- Increased Enzyme induction - Decreased Enzyme inhibition - Decreased Genetic polymorphism of some metabolic enzymes - Liver cirrhosis - CL is generally decreased
- Transporter activity
- Decreased Inhibition of uptake transporters or genetic polymorphism (OATP1B1)
