Elimination Flashcards
What is elimination?
Irreversible removal of drug from the body by all drug removal mechanisms
What are the two main mechanisms under elimination?
- Biotransformation (metabolism)
- Excretion
What is biotransformation (metabolism)?
Irreversible removal of drug by chemical conversion to metabolite
Metabolites can have active properties or be toxic
Biotransformation largely occurs in the liver, with some occurring in GI tract, lung, skin, and kidneys
What is excretion?
Irreversible removal of intact (parent) drug from the body
Excretion is largely completed by the kidney, but can also occur in the liver, lung, saliva, and milk
Are most drugs modified by one of the elimination mechanisms?
No, some are primarily eliminated via biotransformation, others by excretion, and the remaining by both biotransformation and excretion
What is clearance in terms of elimination processes?
It is a measurement of the efficiency of mechanisms involved in drug removal (elimination) from the body
What is the physiological definition of clearance?
Clearance is the volume of blood completely cleared of drug per unit time
What is the general (mathematical) definition of clearance?
Clearance is a proportionality constant relating rate of elimination to the plasma concentration at a given point in time
Cl = rate of elimination/Cp, note Cl is a constant and any changes in plasma concentrations are adjusted for by shifts in the rate of elimination
Refer to slide 5 for calculating systemic clearance from PK parameters
Review slide 7 for an overview of oral clearance
What are the principal elimination pathways for systemic clearance?
Hepatic and Renal
What are the primary mechanisms for hepatic clearance?
Billary excretion (transporters)
Biotransformation (metabolism)
- Phase I (ex. P450)
- Phase II (conjugation enzymes)
What are the primary mechanisms for renal clearance?
- Glomerular filtration (GFR)
- Tubular absorption and secretion
Compare and Contrast
Systemic Clearance (Cls) vs. elimination rate constant (k)
Cls is a primary PK parameter (impacted by physiological state only)
k is a secondary PK parameter (impacted by primary Pk parameters)
k=Cls/Vd, note Cls and Vd are constants and do not change in linear PK systems
What is extraction ratio (E) in terms of elimination?
This is the amount of drug that is removed from the blood by eliminating organs (liver and kidneys)
review slide 13 for equation for extraction ratio
What are the two requirements for drug to be eliminated at eliminating organs?
- Blood must deliver drug yo the elimnating organ (Q)
- Eliminating organ must extract drug from blood (E)
Therefore, Clearance = Q (blood flow) x E (extraction ratio)
What factors affect extraction?
- Drug binding to/partitioning into blood cells
- Drug binding to plasma proteins
- Unbound drug diffusion into the hepatocyte
- Unbound drug excretion
- Unbound drug enzymatic biotransformation
- Blood perfusion rate (Q) to the liver (elimination organ)
What is the rate-limiting step in the elimination of high extraction ratio drugs?
High E (E is greater than 0.7)
Perfusion rate-limited (may need to adjust dose in patients with HF)
What is the rate-limiting step in the elimination of low extraction ratio drugs?
Low E (E is less than 0.3)
Extraction is rate-limiting
Most drugs are low extraction ratio drugs
Do the kidneys generally eliminate lipophilic drugs?
No, lipophillic drugs tend to be eliminated by the liver
The opposite applies to hydrophilic drugs, as they are eliminated by the kidneys
