Drug Distribution Flashcards
Definition of distribution?
reversible transfer of drug between the blood and other tissues in the body
What affects the rate of distribution?
- delivery of drug to tissue by perfusion
- the permeability of tissue membranes
- physicochemical properties of the drug (lipophilic/polar?)
- binding of drug to plasma proteins (only unbound drug crosses membranes)
- binding to acidic phospholipids in the tissue membranes
What is perfusion rate limited distribution?
movement from blood to tissue across the membrane is fast, so the rate of distribution is dependent on the rate at which the blood delivers the drug to the tissues
What types of drugs are prone to perfusion rate limited distribution?
- likely to occur when molecules are small and lipophilic
- perfusion is not the same across tissues, rapid equilibrium is achieved faster in highly perfused organs e.g. kidneys, brain
- slower equilibrium in poorly perfused tissues e.g. skin, adipose, resting muscle
- lipophilic molecules have a high affinity for adipose tissue
What is permeability rate limited distribution?
Distribution into tissues is detemined by the drug being able to cross the membrane between the blood and the tissue
What types of drugs are prone to permeability rate limited distribution?
polar molecules (as well as impermeable membranes e.g. BBB) there may also be active transport involved in the transport
Effects of properties of drugs on the ability to cross the blood brain barrier?
lipophilicity, fraction unbound to proteins, ionisation,
Why is the BBB so hard to cross?
very tight junctions, barrier is at capillary level
- compared to muscle capillary wall, porous to small moleucles. barrier at cellular level
What is the apparent volume of distribution?
(apparent because it can’t be measured directly)
- based on equilibrium concept
- relates the measured plasma drug conc (C) to the amount of drug in the body (A)
V = A/C
Definition of volume of distribution?
Volume that the drug occupies at a concentration equal to that in plasma (litres)
What is the lowest possible volume of distribution?
3L - the volume of plasma
Important note about volume of distribution?
does not refer to a physical volume
What is Cb?
Concentration in the blood (incl cells etc)
What is C?
Concentration in plasma
What is Cu?
Concentration unbound - plasma water (no plasma proteins)
Clincal relevance of volume of distribution?
important PK parameter to determine the loading dose of a drug
Typical volume of plasma?
3L
Typical volume of Extracellular water?
13-16L
Typical volume of interstitial fluids?
10-13L
Typical volume of intracellular water?
25-28L
Typical volume of transcellular water?
0.7-2L
Typical total body water?
40-46L
Examples of drugs with a high volume of distribution?
Quinacrine, chloroquine (10,000-50,,000L)
Examples of drugs with a low volume of distribution?
MAbs, warfarin, tolbutamide
General principles of how types of drugs distribute?
basic drugs tend to have higher Vd, as they bind to acidic phospholipids
acidic molecules tend to reside in the plasma - ionise and bind to plasma proteins
How is digitoxin special in how it distributes?
Vd is 40L, but we know it accumulates highly in cardiac tissue (range within physiological volumes, need to be careful how these are interpreted)
How to determine the fraction of drug in body in plasma?
Plasma volume (i.e. 3L) /Volume of distribution
How to determine the fraction of the drug in the body outside plasma?
1- fraction in plasma
What is subcellular distribution?
Distribution in organelles
What types of molecules tend to distribute in lysosomes?
Cationic amphiphilic drugs
LogP >2, pKa 6.5-11 (e.g. antibody drug conjugates)
Consequences of distribution in the lysosomes?
Reduced ability of the protonated drug to diffuse back into the cytosol - trapped in the lysosome (lungs and liver have a lot of lysosomes)
occasionally the drug target is the lysosomes e.g. antimalarials
- reduced acitivity and off target effects: less efficacy and potential for side effect
- safety issue - phospholipidosis
What is phospholipidosis?
lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues.
General points on plasma protein binding?
a very rapid and usually reversible process
bound drugs cant cross membranes
Which plasma proteins do drugs tend to bind to?
Albumin, a1-acid glycoprotein, globulins
What types of drugs bind to albumin?
acidic (e.g. warfarin) and neutral (e.g. ciclosporin)
What types of drugs bind to a1-acid glycoprotein?
basic drugs
What types of drugs bind to globulins?
Steroids
How to calculate the fraction of unbound drug in plasma?
Concentration unbound / total plasma concentration
How to calculate the fraction of bound drug in plasma?
1 - fraction unbound
What factors can alter fraction unbound?
pregnancy, or some diseases (liver cirrhosis, renal impairment) - expression of plasma proteins may be altered
What does fraction unbound depend on?
- affinity of the drug for the protein
- protein and drug concentration
What is the importance of knowing the fraction of unbound drug?
total plasma conc is usually measured - changes in plasma conc reflect changes in unbound drug conc when fu is constant
only unbound drug can cross membranes and have a pharmacological effect
Examples of drug with v high unbound fraction?
Atenolol, metformin, lithium
Examples of drugs with v low unbound fraction?
Warfarin, Flurbiprofen
How is tissue distribution normally measured?
Inferred from plasma data, rarely measured directly
How does tissue distribution occur?
Unbound molecule corsses membranes and enters the tissue, then can bind to proteins eithin the tissue (equilibrium between Cu in tissue and C bound in tissue
What things does the distribution of a drug within the body depend on?
binding of the drug to both plasma proteins and tissue components
involvement of transporters (influx and efflux)
What coefficient characterises tissue binding?
tissue-to-plasma partition coefficient, Kp
can have a different Kp for each organ (relative to plasma)
What is the volume of aqueous volume outside plasma?
approx 39L
Equation linking the total amount of drug in the body?
A = V•C = Vp•C + Vtw•Ct
Vp = volume of plasma, Vtw = volume outside plasma
What causes high Volume of distribution in terms of tissue distribution?
High fraction unbound in the blood, or low fraction unbound in the tissue (ie extensive tissue binding)
What do hepatic uptaketransporters do in terms of drug disposition?
mediate active uptake of drugs into the hepatocyte
can result in a higher concentration in the liver than the plasma
What do hepatic efflux transporters do in terms of drug disposition?
Excretion of drugs into bile by efflux transporters
Effect on tissue concentrations if active transport/rapid metabolism in cell occurs?
C unbound in plasma ≠ C unbound in tissue
metabolism: Higher conc in plasma than in tissue
efflux: higher conc in plasma than in tissue
Uptake: higher conc in tissue than in plasma
How can Kp be determined?
In vitro - using tissue homogenate or isolated perfused organs
in silico - predictive equations based on physicochemical properties and tissue composition
What is PBPK moedelling?
physiologically based pharmacokinetic modelling
the body is represented as a multi-compartment of individual organ compartments. organ compartments are connected by blood flows in a physiologically meaningful way. physiological parameters can be adjusted for the population you are studying
