BCS Flashcards
What is permeability? What is it influenced by?
The rate at which a drug is transported across a membrane. This is influenced by diffusion and distribution.
Describe permeability in the GI and why this is important.
In the GI, permeability is driven by diffusion. This can be predicted using Fick’s first law, as steady state conditions apply.
This is important because over 80% of drugs are administered orally.
What do terms Cd, C1, C2 and Cr refer to and how is this applied?
Cd is the concentration of solute in the donor compartment.
C1 is the concentration of solute at the start of the diffusion layer (intestinal membrane).
C2 is the conc of solute at the end of the diffusion layer.
Cr is the conc of solute in the receptor compartment.
C1 is not equal to Cd, and C2 is not equal to Cr but Cd and Cr are readily measured so this is usually used in application.
What is the Fick’s law equation in application and the
permeability coefficient equation across a membrane?
J = DKCd/h where J = flux D = diffusion coefficient K = partition coefficient Cd= concentration in donor compartment h = membrane thickness.
dM/dt = PCdS where dM/dt = rate of transfer across membrane P = permeability coefficient Cd = concentration in donor compartment S = surface area of diffusion layer.
What factors control drug permeability?
Overton’s rule: membrane permeability increases with hydrophobicity
Lipinski’s rule of 5: restrictions set for lipophilicity of orally administered drugs, where permeability depends on the log P (partition)
How can extent of absorption be determined? how is this relevant to permeability?
Can be found using mass balance pharmacokinetic studies or F studies (AUCpo/AUCiv).
This tells us extent of drug absorption but not the rate of permeability.
How can intestinal permeability be measured? When is something considered highly permeable?
- in vivo intestinal perfusion studies in animals.
- in vitro or ex vivo experiments with human or animal intestinal tissue
- in vitro permeation across epithelial cell monolayers.
A drug is considered to be highly permeable is >/= 90% of the dose is absorbed into the blood stream.
What is the permeability coefficient lag time?
The lag time is the time required for a drug to penetrate the membrane to establish a concentration gradient within it. The time required to reach steady-state permeability rate.
What is the difference between solubility and dissolution?
Solubility is the extent to which a solute can dissolve in a given amount of solvent at a set temperature whereas dissolution is the rate at which the solute dissolves in a given amount of solvent at a set temperature.
How can solubility profile be measured?
By the shake flask method, where the solubility is measured across a range of pH’s that mimic those present within a biological system (pH 1-7.5).
This is by adding drug till solvent is saturated, system is shaken to ensure maximum dissolution and precipitate is removed.
The dissolved component is measured by UV/vis spec, HPLC or another stability indicating assay.
When is a drug considered highly soluble?
A drug is considered hgihly soluble when the highest strength dose is soluble in 250mL or less of aqueous media over the pH range of 1-7.5
WHen is a drug considered rapidly dissolving?
A drug is considered to be rapidly dissolving when >85% of the labelled amount of drug substance is dissolved within 30 mintues using a USP, in 900mL of buffer.
How are drugs classed? What are these classes?
Based on solubility and permeability.
Class I: high permeability and solubility - well absorbed and rate is fast.
Class II: high permeability, low solubility - F is limited by solvation rate
Class III: low permeability, high solubility - absorption is limited by permeation rate but is solvated quickly.
Class IV: low permeability, low solubility; poor bioavailability.
What is a biowaiver?
A biowaiver is an exemption from conducting human bioequivalence studies. These are eligible for formulations that demonstrate rapid and similar dissolution to a market formulation, high solubility, high permeability, excipients that are immediate release, and a wide therapeutic window.
How can classes be applied to biowaivers?
Most class I drugs are eligible for biowaivers. Some class II and III are available.
