Drug Distribution

Question 1

describe drug distribution

Answer 1

Drug distribution is the reversible passage of drug between tissues, organs and compartments

Question 2

name the major body compartments

Answer 2

• intravascular fluid
• interstitial fluid
• intracellular fluid
• body fat

Question 3

factors that influence drug distribution

Answer 3

drug distribution can be influenced by
- physiochemical properties of a drug
- local pH, blood flow, and transport
- reversible binding to plasma proteins
- permeability of blood-tissue barrier

Question 4

name important plasma proteins for drug binding

Answer 4

a1 acid glycoprotein

human serum albumin (HSA)

Question 5

describe factors that contribute to poor drug distribution into the brain

Answer 5

• membrane permeability
• Absence of fenstrations on BBB tissue impacts drug diffusion thorugh tissue walls

Transporters on the BBB have more sensitive efflux transporters that can turn drug away e.g MDR1

Question 6

Describe the role of
transporters in hepatic uptake of drugs

Answer 6

Identified transporters like OCT1/2 are vital in mediating transport across membranes

Question 7

describe volume of distribution

Answer 7

an indication of the extent to which a drug is distributed to the tissues of the body and is the theoretical volume needed to dilute the total amount of drug in the body at a given time to achieve the measured plasma concentration

determines loading dose of drug

Question 8

Describe vol of dis relationship with relationship with plasma concentration and body
compartment(s)

Answer 8

Large bodies with a higher plasma conc. will have a lower volume of distribution

Question 9

distinguish between one compartment model and two compartment
model

Answer 9

One compartment model:
- drug is held within one compartment and then excreted
- measurable by finding the conc. of drug within that compartment
- Ct = C0 ∙ e−kt

Two compartment model
- Considers that Drugs are held within centralised well perfused compartments and peripheral less well perfused drugs
- fast and slow phase
- fast = distribution
- Slow = elimination

Question 10

predict the body compartment(s) into which a drug is distributed for an average male adult of
70 kg

Answer 10

60% of body weight is total body water - 70* 0.6 = 42L of water

Drugs with a high volume of dis will accumulate in tissues and TBW (Volumes of 100+)

Drugs with a distribution of around 40L remain in TBW

Drugs with a Vd of 10-20 is likely in extracellular fluid

Drugs with a Vd of 5 or less will be in the plasma (high conc.)

Question 11

Impact of solubility of a drug on distribution (physio-chemical properties)

Answer 11

• Hydrophilic drug stays in extracellular environments

Lipophilic drugs can easily pass through membranes and penetrate tissues

Highly lipophilic drugs accumulate in adipose tissue

Question 12

How does local pH affect drug distribution

Answer 12

many drugs are either weak acids or weak bases
- Ionised drugs cannot pass freely across membranes
- Causes ion trapping

Question 13

How does blood flow affect drug distribution

Answer 13

Drug distribution occurs initially in the central compartment (plasma and highly perfused tissues) before distribution into peripheral compartments (poorly perfused tissues) e.g. resting skeletal muscles, body fat

Question 14

How does tissue binding affect drug distribution

Answer 14

• Drugs can have affinities for specific tissues or organs e.g. calcium will accumulate in calcium rich tissues
• Highly lipophilic drugs will accumulate in fat

Question 15

How does plasma protein binding affect drug distribution

Answer 15

decreases free drug conc. Impacting:
* distribution into tissues
* drug concentration at site of action
* therapeutic effect
* hepatic metabolism
* renal clearance

Question 16

Plasma binding protein prone drug types

Answer 16

Lipophilic drugs are prone to plasma protein binding

Question 17

How does permeability of blood-tissue barrier affect drug distribution

Answer 17

Absence of fenstrations on BBB tissue impacts drug diffusion thorugh tissue walls
Transporters on the BBB have more sensitive efflux transporters that can turn drug away

Question 18

Describe the role of
transporters in brain penetration of drugs

Answer 18

Transporter returns drugs to circulation

• efflux transporters, e.g., MDR1, BCRP - overexpression in brain tumour cells → drug efficacy ↓