Drug Distribution Flashcards
What is drug distribution?
is the reversible transfer of drug from one site to another within the body
blood circulation enables efficient drug distribution
elimination cells have a high amount of blood flow like kidney or liver
3l in plasma to 15l extracellular fluid to 40l total body water
The nature of transport is
reversible
Important and considered in PK models
transcellular diffusion
through the cell
passive
paracellular diffusion
through tight junction
movement dependent on the tightness of the junction
passive
facilitated transcellular transport
through the cell
passive
Diffusion
(especially, passive): ficks law
smaller drug molecular weight will diffuse faster
drug lipophilicity- more lipophilic is the better its is in transporting into the cell membrane
drug ionization- more ionized less lipophilic less into the cell membrane
un charged diffuse better
if the plasma is bound to drug it will not move across the membrane
membrane thickness- smaller faster
Carrier-mediated transport
Selective (drug structure)
Competition
Saturation
Influx vs Efflux
The graph compares the rates of drug absorption, as function of drug concentration, of a drug absorbed by passive diffusion and a drug absorbed by a carrier-mediated transport.
A: Passive diffusion. The rate of drug absorption increases linearly to drug concentration. This is a first-order process because it depends on drug concentration.
B: Carrier-mediated transport. The rate of drug absorption increases with drug concentration until carrier molecules are saturated (fully occupied). At higher concentrations, the process becomes zero-order.
capillaries to interstitial fluid
capillaries are leaky so up to 5000g/mol can leave the vessel easily
Capillary membranes are
generally very permeable. Transport is independent of drug lipophilicity, charge, and molecular size (up to 5000 g/mol). Usually easy paracellular transport. But we don’t forget the…
Blood-Brain barrier
Capillaries surrounded by a layer of glial cells with very tight junctions
Thick lipid layer that slows diffusion and penetration of water-soluble and polar drugs
P-glycoprotein (efflux transporter) presence
interstitial fluid to cell
Passage across cell membranes very dependent on: (a) drug physicochemical properties (size, charge, lipophilicity) and/or
(b) the drug being a substrate for influx / efflux transporters
drug-protein binding
Drugs may interact with plasma or tissue proteins. The formation of drug-protein complex is often named drug-protein binding. The process is fast and usually reversible
Volume of Distribution or V OR Vd
the apparent volume into which a drug distributes in the body once the equilibrium of distribution has been achieved.
b) also defined by the expression:
v= amount of drug in the body / concentration of drug in the plasma
V is used to:
Relate the amount of drug in the body with the drug plasma concentration
Estimate the dose required to achieve a given concentration “C required”:
Dose = V * C required
Protein binding
𝑉_𝐷= 𝑉_𝑝+ 𝑉_𝑡 (𝑓_𝑢/𝑓_𝑢, 𝑡𝑖𝑠𝑠𝑢𝑒) )
When fu increases (more drug free, not bound to plasma proteins), the VD increases, because there is more drug available to cross into the tissue. Of, course, the opposite holds true if fu,tissue increases (VD decreases; more drug available to cross into the plasma)
Partition coefficient
𝑉_𝐷= 𝑉_𝑝+ 𝑉_𝑡 𝑃
The higher the P (more lipophilic drug), the higher the VD (drug is able to cross membranes)
% of drug in plasma
%_𝑝= 𝑉_𝑝/𝑉_𝐷 𝑥 100
A drug with high VD distributes into tissues (low % in plasma)
A drug with low VD does not distribute extensively into tissues (high % in plasma)
% of drug in tissues
%_𝑡= 〖𝑉_𝐷 −𝑉〗_𝑝/𝑉_𝐷 𝑥 100
A drug with high VD distributes into tissues (high % in tissues)
A drug with low VD does not distribute extensively into tissues (low % in tissues)
How long does distribution last?
Drug distribution is a two-stage process and consists of:
Delivery of the drug to the tissue by the blood
(controlled by blood flow)
Diffusion or uptake of drug from the blood to the tissue
(controlled primarily by drug properties)
The overall rate of distribution is controlled by the slowest step
Perfusion-Rate Limitation
Small & lipophilic molecules diffusing across most membranes in the body.
Access to tissues will be limited by blood flow. Well-perfused tissues will take up the drug much faster than poorly perfused.
Changes in blood flow will modify distribution.
If the perfusion rate increases or the tissue/plasma ratio decreases to The larger the KT,
The larger the KT, to The faster the distribution
If the perfusion rate increases or the tissue/plasma ratio decreases to The larger the t1/2
The larger the t1/2 to The slower the distribution
transporters from blood to tissues, into cell and back
influx or uptake
transports drugs into the cell
apical side
lumen
basolateral
blood side
as the partial coefficient increases
the drug becomes more lipophilic permeability in the BBB increases
even with a high partition coefficient the permeability can be low why is that ?
they are substrates for an influx transporter P glycoprotein.
so the it passes through the cell membrane but gets then put out so cant accesses the brain. its actively excreted out of the brain
the free concentration in tissue
is the same as plasma
total concentration of tissue as plasma is
dependent on how much is bounds and to which
what is the body exposure
concentration at the given time
area under the curve- doesn’t capture the concentration at one time it does it as different times
highest peak concentration
if we use volume distribution
we account for the drug distribution outside of plasma
Hydrolysis of Procaine Hydrochloride
Procaine hydrochloride undergoes hydrolytic degradation, accelerated in alkaline conditions. UV-visible spectroscopy is used to monitor its degradation
Paracetamol
is a common pain reliever and antipyretic.
Its absorption depends on gastric emptying rate, which can vary.
Rapid-absorption formulations aim for faster and more consistent pain relief.
Disintegrants are added to tablets
to promote their break-up, which enhances drug release
