L4 Drug Distribution

Question 1

Drug distribution

Answer 1

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

Question 2

What does it mean if the body is compartmentalised

Answer 2

the body is compartmentalised - drugs need to cross lipid membrane to move from one compartment to another compartment

Question 3

What can influence drug distribution

Answer 3

• Physiochemical properties of a drug
• Local pH, blood flow and transport
• reversible binding to plasma proteins

Question 4

Very lipophilic drugs will accumulate where

Answer 4

In fat

Question 5

Factors that influence drug distribution (vii)

Answer 5

• Solubility of a drug
• local pH
• blood flow
• Tissue binding
• Plasma protein binding
• permeability of blood tissue barrier
• expression of transporters

Question 6

Factors that influence drug distribution
(i) solubility of a drug

Answer 6

• hydrophilic drugs stay in the extracellular compartment
• lipophilic drugs -> cross cell membranes and penetrate tissues
• highly lipophilic drugs are distributed into tissues & accumulate in fat - obesity complicates drug distribution

Question 7

(i) solubility of a drug Ethanol

Answer 7

• a CNS depressant - lipid-soluble enough to cross the blood-brain barrier
• distribution is dependent on the relative water content of tissues

Question 8

Factors that influence drug distribution
(ii) local pH

Answer 8

• many drugs are either weak acids or weak bases
• pH-dependent ionisation - pH partition and ion trapping

Question 9

Factors that influence drug distribution
(iii) blood flow

Answer 9

• Drug distribution occurs initially in the central compartment (plasma and highly perfused tissues) before distribution into peripheral compartments (poorly perfused tissues)

Question 10

Well perfused

Answer 10

• drugs distributed here first
  heart, brain, liver, lungs

Question 11

Poorly perfused

Answer 11

resting skeletal muscles, fat

Question 12

Factors that influence drug distribution
(iv) tissue binding

Answer 12

(a) drugs can accumulate in specific tissues/ organs

(b) highly lipophilic drugs accumulate in fat

Question 13

( Tissue binding) Tetracyclines

Answer 13

Tetracyclines* have a high affinity for binding calcium - and slowly accumulate in bones and teeth
- Tetracyclines in pregnancy (TGA category D drug) can cause birth defiects young children

Question 14

(Tissue binding) Thiopental and why not given continuously

Answer 14

• an intravenous general anaesthetic
• There is not any continuous giving of this anaesthetic bc it is highly lipophilic this means that it will slowly distribute in fat (as storage) and overtime the drug will return to systemic circulation at a time when the drug is not needed. It would maintain the plasma concentration of the drug at an undesirable level and decline slowly.
• will act on the brain again and create a hangover effect.

Question 15

Factors that influence drug distribution
(v) plasma protein binding

Answer 15

Plasma protein act as carriers for endogenous compounds and
xenobiotics
* binding is reversible
* lipophilic drugs are prone to plasma protein binding

Question 16

Xenobiotics

Answer 16

A xenobiotic is a general term referring to any chemical foreign to an organism or, in other words, any compound not occurring within the normal metabolic pathways of a biological system

Question 17

free (unbound) drug concentration can

Answer 17

• distribution into tissues
• drug concentration at site of action
• therapeutic effect
• hepatic metabolism
• renal clearance

Plasma protein binding decreases the free drugs and decline those activities

Question 18

Name 2 important drug binding plasma proteins

Answer 18

α1 acid glycoprotein
human serum albumin (HSA)

Question 19

α1 acid glycoprotein

Answer 19

• a glycosylated protein synthesised in the liver
• bind basic drugs

Question 20

Human serum albumin (HSA)

Answer 20

• a 66 kDa protein synthesised in the liver; the most abundant protein (~ 600 mM) in human
  plasma
• binds many acidic drugs
• three homologous domains (I, II and III)
• each consists of A and B subdomains
• two important drug-binding sites
  o Sudlow’s site I (in IIA) - e.g., warfarin
  o Sudlow’s site II (in IIIA) - e.g., ibuprofen

Question 21

Factors that influence drug distribution
(vi) permeability of blood-tissue barrier

Answer 21

• endothelial cell layer
  
  • fenestrations facilitate solute exchange between blood plasma and interstitial fluid
• basal membrane - a matrix of proteins with spaces filled with water
  
  • free passage to small molecules < 10 kDa
  • plasma protein-bound drugs and macromolecules are retained

Question 22

Fenestrations

Answer 22

Any small opening

Question 23

Blood-brain barrier (BBB)

Answer 23

• endothelial cell layer
  
  • no fenestrations but tight junctions
• basal membrane
• glial cells joined by tight junctions
• protective role enhanced by transporters

Question 24

Factors that influence drug distribution
(vii) expression of transporters

Answer 24

• major organs - intestine, liver, kidney
• organs with barrier functions - brain, placenta

Question 25

Drug distribution *(vii) expression of transporters* Liver

Answer 25

Liver * first point of contact following intestinal absorption * accumulate and detoxify xenobiotics - transporters on the basolateral membrane of hepatocytes - rich in drug-metabolising enzymes (to detoxify)

Question 26

Transporters and hepatic drug uptake

Answer 26

slides

Question 27

Transporters and brain penetration

Answer 27

* transporter-mediated uptake of nutrients and certain drugs to brain. * transporter returns drugs to circulation (capillaries) - efflux transporters, e.g., MDR1, BCRP - overexpression in brain tumour cells → drug efficacy ↓

Question 28

A poor imatinib (a tyrosine kinase inhibitor) distribution into the brain due to efflux. What is the role of MDR1 in efflux of imatinib?

Answer 28

- brain/blood concentration ratio ↑ in the presence of an MDR1 inhibitor - brain/blood concentration ratio ↑ in MDR1 knockout mice (red arrows in slides)

Question 29

Volume of distribution

Answer 29

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

Question 30

Volume of distribution reflects and determines

Answer 30

reflects the extent to which the drug has moved from the plasma into the tissues determines the loading dose of a drug - loading dose = Vd x desired plasma concentration

Question 31

Highly protein-bound drugs

Answer 31

- stay in plasma - high plasma concentration and small Vd

Question 32

Highly lipophilic drugs

Answer 32

- distribute into fat - low plasma concentration and large Vd

Question 33

VOl of distribution

Answer 33

Vol of solvent that would contain the total body content of the drug (Q) at the conc equal to the measured plasma conc (Cp), Vd = Q/Cp | For drugs that accumulate outside plasma compartment the Vd may exceed total body vol

Question 34

Vd greater than total body vol

Answer 34

A VD greater than the total volume of body water (approximately 42 liters in humans) is possible, and would indicate that the drug is highly distributed into tissue

Question 35

Major body compartments (4)

Answer 35

1. Intravascular fluid 2. Interstitial fluid 3. Intracellular fluid 4. Body fat

Question 36

One compartment model vs two compartment model

Answer 36

A one-compartment model may be used for drugs that rapidly equilibrate with the tissue compartment, e.g, aminoglycosides. A two-compartment model should be used for drugs that slowly equilibrate with the tissue compartment, e.g, vancomycin.

Question 37

Two compartment model

Answer 37

Drugs are absorbed into the central compartment (blood), distributed from the central compartment to the peripheral compartment (tissues), and eliminated from the central compartment