Flashcards in PK 3 Deck (20)
What is the benefit of PBPK?
Very useful for predicting PK across species
Using PBPK how can Vd be predicted?
By a knowledge of drug plasma protein and tissue binding
Using PBPK how can CL be predicted?
Using allometry or in vitro enzymes kinetics
What is Kleibers law?
Mass specific metabolic rate needed to sustain an organism decreases with body weight to the 1/4 power
i.e. Mass specific metabolic rate = constant x BW^0.25
What impact does allometry have on clearance?
-The smaller the animal the greater the drug clearance
- Larger an animal is the lower the blood flow and as plasma clearance is dependent on blood flow clearance is also less in larger animals.
-BUT application of this theory less reliable on drug metabolism clearance due to enzymes- different species have different enzymes
What is intrinsic clearance?
The enzyme mediated clearance that would occur without physiological limitations
How do you calculate CLintrinsic?
What limits the clearance of high clearance drugs?
How do you calculate the clearance for low clearance drugs?
fraction unbound x intrinsic clearance of the liver
What are the reasons for variation in PPB?
- Elderly/ neonates have less proteins
- Disease states can affeect concentration
- Drugs may be displaced from plasma proteins by other drugs that have a higher affinity
What will happen to CL and Vd if PPB increases?
They will decrease
What is free drug concentration?
It is the effective concentration->it drives the effects. So if PPB decreased causing an increase in CL and Vd then free drug conc would stay the same.
From a clinical point of view is a change in PPB an issue?
- Rapid IV bolus
- Parenteral administration of displaced drug with high organ extraction ratio
- Therapeutic drug monitoring and drug displacement from plasma binding site
What is the problem with rapid IV bolus?
-The rapid admin of the displacement agent could cause free conc to increase due to rapid displacement of displaced drug before redistribution occured.
-It will equilibriate and then not an issue
-e.g. sulfamide + bilirubin= Kernicterus
Explain therapeutic drug monitoring and drug binding displacement from plasma binding
Phenytoin + Valproic acid (Ctotal= 15)
- No dosage adjustment needed though because although Ctot decreases, fu Increases so C free doesn't change
Describe the advantages controlled release drug therapy
Similar kinetics to IV infusion (0 order)
Reduced risk of breaching therapeutic window
Drug delivery period can be over several months from 1 administration
What is the depot effect?
- Drug diffusion/ release= K x (drug conc at depot surface)
-K = the drug release constant
-Works like a bar of soap, outside film dissolves at a constant rate so specific amount of drug administered and the rest is sequestered inside.
What is the Paratect bolus morantel system>
-Delivers morantel tartare for up to 90 days
- Controled release occurs through discs at the ends and the rest is sequestered inside.
How do spot on anthelmintics work as controlled release drugs?
-They are oil based as so the drug is sequestered inside sebaceous glands and released with sebum at a constant rate