Methotrexate Flashcards
Action of Methotrexate- draw MOA
- Antagonist of folic acid; inhibits DHRF; prevents formation of tetrahydrofolate; inhibition of DNA and RNA.
What is MTX used for?
- For acute lymphoblastic leukemia, meningeal leukemia and rheumatoid arthritis.
Problems with methotrexate?
- Poor solubility due to aromatic rings and neutral compound; both basic and acidic groups; more soluble in blood stream in salt form, as it is charged
- Low permeability (ClogP=0.53)
- Prolonged exposure to drug needed as it only kills actively dividing cells.
- Short plasma half-life of 2-10hr
- Non-specific delivery
- Development of resistance through receptor mediated pathway, the cells that take up less are the ones that are going to survive.
MTX formulations
• Oral Tablets; methotrexate sodium; oral route becomes saturated due to receptors in GI tract. Peak conc after 1-2 hours
- Low doses common for arthritic conditions
• Intramuscular injection: used for rheumatoid arthritis, better absorption than oral, peak concentration (30-60 minutes) similar to IV but slower drug absorption and more prolonged exposure. Distribution to tissues and extracellular fluid
• Parental Route is needed to achieve high dose, but bioavailability does not increase with increasing doses above threshold level.
What clearance phase does methotrexate have?
Triphasis
How can the toxicity of methotrexate be enhanced?
- Penetrates ascitic fluid and effusions; can act as depot and enhance toxicity
What is the terminal elimination half-life and half-life
3-10 hours
8-15 hours
How does MTX enter cells?
• Enters cells via active transport mechanism: converted intracellularly to polyglutamate conjugates, which is not actively exported, processing of this can liberate MTX, hence MTX can remain in the body for several months, particularly in the liver
How does resistance occur?
If decreased transport and increased efflux and impaired poly(glutamylation) then development of resistance can occur.
- Can select for resistance phenotypes
- Impairment of drug import into cells and increase in drug export can generate resistance
- Local administration of soluble MTX sodium can lead to rapid transport through capillaries into circulatory system
What are the practical issues of MTX
- Variability
- Renal elimination
- Protein binding
- Aspirin and NSAIDs
- Crystal formation
- Overdose
- Resistance
How is methotrexate variable?
- affected by age, renal and hepatic function
- limited lipid solubility, does not diffuse across lipid membranes
- not transported into CSF after oral of IV administration
Renal elimination and methotrexate
- Glomerular filtration
- Active tubular secretion
- Toxicity dependent on duration of exposure
How does protein binding affect MTX?
- 50% of MTX bound to plasma proteins, excreted less quickly; variation between oral and IV elimination rates
How do NSAIDs effect MTX?
- Displace MTX from protein; increased serum levels of free MTX
- Inhibit MTX secretion in proximal tubule
- Reduce renal clearance, increasing blood levels
- Increase in duration, thus exposure and hence toxicity.
How are crystals formed with MTX?
- High dose MTX -> Supersaturation of urine with methotrexate and its metabolites; crystal formation; can cause intrarenal obstruction leading to renal failure.
- Risk factors for the formation: acid urine, volume depletion, renal impairment.
- Minimize this by hydration and urine alkalization with sodium bicarbonate or acetazolamide.
