Distribution Principles

Question 1

What are the factors determining the rate and extent of distribution?

Answer 1

Q=tissue/organ blood flow rate
Ca=arterial concentration
Cv=venous concentration
Kp=partition ratio (Ct/Cv)
Ct=tissue concentration
Cu=free concentration
Cb=bound concentration
tissue perfusion, drug permeability characteristics, binding/partitioning

Question 2

What is distribution equilibrium?

Answer 2

no net movement of drug between blood and tissue
-drug is being eliminated and distributed

Question 3

How is distribution equilibrium determined?

Answer 3

distribution half-life
=0.693 x Kp/(Q/Vt)

Question 4

When would approach to tissue equilibrium take longer?

Answer 4

poorer perfusion rates
higher tissue partitioning of the drug

Question 5

Rate of distribution is either ___ rate-limited or ___ rate-limited.

Answer 5

perfusion rate-limited
permeability rate-limited

Question 6

Describe perfusion-rate limited drugs.

Answer 6

tissue membrane presents no barrier to drug distribution (rapid equilibration)
only tissue blood perfusion rate limits movement between blood and tissue
small, lipophilic drugs

Question 7

Describe permeability-rate limited drugs.

Answer 7

membrane (polarized epithelium) is a barrier to drug distribution (slow equilibration)
large or polar drugs

Question 8

What are the factors that govern perfusion-rate limited distribution?

Answer 8

blood flow rate (Q)
drug affinity for tissue (Kp)
governs how drug is distributed and how much drug accumulates in tissue

Question 9

Provide examples of well-perfused tissue and poorly-perfused tissue.

Answer 9

well-perfused:
-lungs, kidney, liver, heart, brain
poorly-perfused:
-muscle, fat, bone, skin

Question 10

How quickly is distribution equilibrium approached when Kp is low and Q is high?

Answer 10

distribution equilibrium is approached quick

Question 11

How quickly is distribution equilibrium approached when Kp is high and Q is low?

Answer 11

distribution equilibrium is approached slowly

Question 12

What is the slow process for permeability rate-limited distribution?

Answer 12

permeation by passive diffusion or carrier-mediated processes

Question 13

What is the significance of Kp?

Answer 13

influences time to equilibration
-higher Kp: longer to DE, slower release from tissue

Question 14

What are the factors governing extent of distribution?

Answer 14

tissue blood flow
-determining rate and extent of drug access
tissue blood volume
-volume of blood available to hold drug in tissue
-greater vascularization, larger the blood volume and greater potential for rapid and extensive distribtution
partitioning
-ratio of drug concentrations in tissue and in blood (Kp)
-higher the ratio, greater the tissue concentration
binding
-drugs reversibly bind plasma and/or tissue proteins to influence availability of drug to site of action, extent of distribution, availability of drug for elimination
partitioning
-drug may partition into blood cells and into membranes/fats
apparent volume of distribution

Question 15

What are the two main factors that can determine rate of distribution?

Answer 15

perfusion rate-limited
permeability rate-limited
drugs fall into one category or the other

Question 16

What is the apparent volume of distribution?

Answer 16

a measure of the extent of drug distribution
-an indirect measure of tissue binding
a proportionality constant relating drug concentration in blood or plasma to amount in the body
-the volume of fluid that drug appears to distribute into

Question 17

What is a large Vd and what does this mean?

Answer 17

> 0.6L/kg
=means more drug is in tissue

Question 18

What is a simplified definition of volume of distribution?

Answer 18

extent to which drug stays in plasma
volume that would contain the total body content of a drug at a conc equal to that in plasma

Question 19

What is the conceptual model of Vd?

Answer 19

Vd=Vb+Vt(fu(b)/fu(t)

Question 20

What are the factors that influence Vd?

Answer 20

variation in binding parameters (Kd, nP)
competitive binding displacements
relative pH of tissue and fluid compartments
blood flow
barrier integrity
body weight and composition

Question 21

What is the equation for loading dose?

Answer 21

LD=Css,ave x Vd/S x F

Question 22

Why are variations in binding parameters (Kd, nP) an important influence on Vd?

Answer 22

interindividual differences in capacity (nP) and affinity (Kd) for binding to plasma protein (or tissue protein) results in differences in fu(b)
influences free concentration of drug at site of action (biophase)

Question 23

What are the causes of variation in binding parameters (Kd, nP)?

Answer 23

genetic variations
stage of development
disease states
-uremia will alter affinity
-hypoalbuminemia will alter capacity

Question 24

Why do drug-drug interactions impact Vd?

Answer 24

competition for the same binding sites between two highly protein bound drugs
-immediate effect may be potentiation of displaced drug
significant only if large fraction of drug originally present in plasma compartment

Question 25

Which endogenous molecules can have an impact on Vd?

Answer 25

bilirubin -conditions causing reduced bilirubing conjugation may lead to bilirubinemia -highly bound to albumin, so acts as a displacer free fatty acids -highly bound to albumin and has high affinity, so acts as a displacer

Question 26

For significant binding displacement to occur, what characteristics must the displacer show?

Answer 26

high affinity for the protein bind at the same site or affect the binding site (conformation) of the drug to be displaced be present in sufficiently high concentrations to saturate the binding capacity -binding capacity is a limiting factor

Question 27

How does pH of tissue and fluid compartments influence Vd?

Answer 27

affects ratio of total concentration -unionized, unbound concentrations are in equilibrium ion trapping phenomenon

Question 28

What is the impact of CO on Vd?

Answer 28

cardiac output determines tissue perfusion

Question 29

What might you expect to happen to Vd with a reduced CO?

Answer 29

decreased tissue perfusion -decreased Vd for drugs extensively distributed increased Vd for drugs distributed in total body water

Question 30

How does exercise impact blood flow?

Answer 30

increase in blood flow to muscle alters fraction of drug reaching muscle tissues

Question 31

How does blood loss impact distribution?

Answer 31

vasoconstriction of large veins redirects blood to needed areas and this will alter distribution

Question 32

What is the impact of disease states on distribution?

Answer 32

loss of tissue barrier integrity allows for greater penetration of drug into tissues -inflammation -burns (skin permeability)

Question 33

Why is transporter expression important in distribution?

Answer 33

facilitated diffusion and active transport may be determinants of tissue uptake/efflux

Question 34

What is the relationship of Vd and body weight?

Answer 34

Vd often proportional to body weight -if drug does not partition into fat, Vd proportional to LBW -if drug partitions into fat, Vd related to TBW