Pharmaceutics 4 - Low and High Dose Methotrexate Flashcards
What is methotrexate mechanism of action?
Antagonist of folic acid, immunosuppressant properties
Inhibits DHFR (dihydrofolate reductase)
Prevents the formation of tetrahydrofolate which is necessary for purine and pyrimidine synthesis
Cell cycle specific inhibition
When is methotraxate used?
Management of acute lymphoblastic leukaemia (ALL)
Prophylaxis and treatment of meningeal leukaemia
Psoriasis (not UK) and rheumatoid arthritis (low dose)
What is a low dose of MTX?
<100mg / m2
What is a moderate dose of MTX?
100mg - 1g / m2
What is a high dose of MTX?
Individual doses of > 1g / m2
Why is oral MTX delivery rarely associated with toxicity?
Absorption of MTX is an active process so in an overdose saturation occurs and only a certain no. of receptors permit entry to cells
What is the permeability of MTX like?
Low permeability (logP = 0.53)
More soluble in bloodstream in salt form; Log P -1.85
What are the problems with sub-therapeutic doses of MTX?
Non therapeutic
Increased risks of resistance developing
Why is prolonged exposure of MTX needed?
Only kills actively dividing cells
What active ingredient is found in oral formulations of MTX?
Methotrexate sodium
More soluble in blood stream in salt form
When is oral formulation of MTX used?
Arthritic conditions
When are I.M MTX injections used?
In rheumatoid arthritis (lower doses than in anti-cancer)
What are the benefits of MTX I.M injection?
Better absorption than by oral route (no saturation of receptors and well perfused)
Slower absorption and more prolonged exposure to drug than IV administration.
Why are parenteral routes needed rather than oral routes in high doses of MTX?
Anticancer doses normally high, parenteral route needed because oral route is saturable - the F does not increase with increasing doses about a certain threshold
Where are low dose oral MTX absorbed?
Mainly absorbed from the GI tract?
Which route of administration is rapidly and completely absorbed?
Intramuscular
What is ascitic fluid?
MTX penetrate ascitic fluid Ascitic fluid (abnormal) accumulation of fluid in the abdominal (peritoneal) cavity.
What is the consequence of MTX penetrating ascitic fluid and effusions?
Can act as a deposit (poor control of distribution) and enhance toxicity
What kind of clearance from plasma is shown by MTX?
Triphasic clearance
How does MTX enter cells?
How does it stay there?
Active transport mechanism
MTX is converted intracellularly into polyglutamate conjugates - this conjugate form ‘MTX=pGlu’ is not actively exported / pumped back out.
Intracellular processing of this conjugate then releases MTX
Hence, MTX can remain bound for several months in the body, especially in the liver.
Accumulation in the liver - long term toxicity.
What are some of the factors that make MTX pharmacokinetics highly variable?
Affected by age, renal and hepatic function
What is MTX solubility like?
Poor / limited lipid solubility; does not diffuse across lipid membranes (needs transporters).
Also, not transported into CSF after oral or IV administration.
What is the main route of administration for MTX?
Renal - glomerular filtration, active tubular secretion.
What is toxicity mostly dependent on?
Duration of exposure more than administered dose
The accumulation of polyglutamate form (metabolism slow)
What are the practical issues associated with MTX?
MTX can bind to proteins; approx 50% bound, (unpredictable variation)
There is a variation between oral and IV early elimination rates.
What does MTX interact with?
NSAIDs and aspirin;
Displace MTX from protein so increase serum levels of free MTX
Inhibit MTX secretion in proximal tubule
Reduced renal clearance, increasing blood levels
Increased duration of MTX exposure overall
What is a problem associated with high dose MTX and supersaturation?
Supersaturation of the urine with MTX and metabolites
Acidic and crystallised urine; uncomfortable and also a sign of renal failure.
Crystals can cause intrarenal obstruction and lead to possible acute renal failure.
What are the risk factors associated with MTX crystal formation in high dose administration?
Acid urine, volume depletion, renal impairment
How can we minimise MTX nephrotoxicity?
Minimise with hydration and urinary alkalinisation
- sodium bicarbonate or acetazolamide
What happens to F as oral dose increases?
Percentage F falls
In the instance of MTX IV overdose what can be done?
Antidote folinic acid (Leucovorin) given intravenously
Timing is critical - efficacy drops rapidly with time after overdose
Need to maintain high hydration (avoid acidic urine)
Does MTX cross the BBB?
In high dose MTX it does cross the BBB
- Danger of severe damage / death if incorrectly dosed
How can resistance develop?
Intervention in RNA and DNA synthesis pathways select for resistant phenotypes.
Impairment on import of MTX into cells and increased drug export can generate resistance.
