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

reversible Important and considered in PK models

through the cell passive

through tight junction movement dependent on the tightness of the junction passive

through the cell passive

(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

Selective (drug structure) Competition Saturation Influx vs Efflux

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 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

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

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

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

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)

𝑉_𝐷= 𝑉_𝑝+ 𝑉_𝑡 𝑃 The higher the P (more lipophilic drug), the higher the VD (drug is able to cross membranes)

%_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)

%_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)

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

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

transports drugs into the cell

lumen

blood side

the drug becomes more lipophilic permeability in the BBB increases

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