L4 Drug Distribution Flashcards
Drug distribution
Drug distribution is the reversible passage of drug between tissues, organs and compartments
What does it mean if the body is compartmentalised
the body is compartmentalised - drugs need to cross lipid membrane to move from one compartment to another compartment
What can influence drug distribution
- Physiochemical properties of a drug
- Local pH, blood flow and transport
- reversible binding to plasma proteins
Very lipophilic drugs will accumulate where
In fat
Factors that influence drug distribution (vii)
- Solubility of a drug
- local pH
- blood flow
- Tissue binding
- Plasma protein binding
- permeability of blood tissue barrier
- expression of transporters
Factors that influence drug distribution
(i) solubility of a drug
- 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
(i) solubility of a drug Ethanol
- a CNS depressant - lipid-soluble enough to cross the blood-brain barrier
- distribution is dependent on the relative water content of tissues
Factors that influence drug distribution
(ii) local pH
- many drugs are either weak acids or weak bases
- pH-dependent ionisation - pH partition and ion trapping
Factors that influence drug distribution
(iii) blood flow
- Drug distribution occurs initially in the central compartment (plasma and highly perfused tissues) before distribution into peripheral compartments (poorly perfused tissues)
Well perfused
- drugs distributed here first
heart, brain, liver, lungs
Poorly perfused
resting skeletal muscles, fat
Factors that influence drug distribution
(iv) tissue binding
(a) drugs can accumulate in specific tissues/ organs
(b) highly lipophilic drugs accumulate in fat
( Tissue binding) Tetracyclines
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
(Tissue binding) Thiopental and why not given continuously
- 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.
Factors that influence drug distribution
(v) plasma protein binding
Plasma protein act as carriers for endogenous compounds and
xenobiotics
* binding is reversible
* lipophilic drugs are prone to plasma protein binding
Xenobiotics
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
free (unbound) drug concentration can
- 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
Name 2 important drug binding plasma proteins
α1 acid glycoprotein
human serum albumin (HSA)
α1 acid glycoprotein
- a glycosylated protein synthesised in the liver
- bind basic drugs
Human serum albumin (HSA)
- 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
Factors that influence drug distribution
(vi) permeability of blood-tissue barrier
- 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
Fenestrations
Any small opening
Blood-brain barrier (BBB)
- endothelial cell layer
- no fenestrations but tight junctions
- basal membrane
- glial cells joined by tight junctions
- protective role enhanced by transporters
Factors that influence drug distribution
(vii) expression of transporters
- major organs - intestine, liver, kidney
- organs with barrier functions - brain, placenta
Drug distribution (vii) expression of transporters Liver
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)
Transporters and hepatic drug uptake
slides
Transporters and brain penetration
- 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 ↓
A poor imatinib (a tyrosine kinase inhibitor) distribution into the brain due to efflux. What is the role of MDR1 in efflux of imatinib?
- brain/blood concentration ratio ↑ in the presence of an MDR1 inhibitor
- brain/blood concentration ratio ↑ in MDR1 knockout mice (red arrows in slides)
Volume of distribution
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
Volume of distribution reflects and determines
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
Highly protein-bound drugs
- stay in plasma
- high plasma concentration and small Vd
Highly lipophilic drugs
- distribute into fat
- low plasma concentration and large Vd
VOl of distribution
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
Vd greater than total body vol
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
Major body compartments (4)
- Intravascular fluid
- Interstitial fluid
- Intracellular fluid
- Body fat
One compartment model vs two compartment model
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.
Two compartment model
Drugs are absorbed into the central compartment (blood), distributed from the central compartment to the peripheral compartment (tissues), and eliminated from the central compartment
