Pharmaceutics 4 - Low and High Dose Methotrexate

Question 1

What is methotrexate mechanism of action?

Answer 1

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

Question 2

When is methotraxate used?

Answer 2

Management of acute lymphoblastic leukaemia (ALL)
Prophylaxis and treatment of meningeal leukaemia
Psoriasis (not UK) and rheumatoid arthritis (low dose)

Question 3

What is a low dose of MTX?

Answer 3

<100mg / m2

Question 4

What is a moderate dose of MTX?

Answer 4

100mg - 1g / m2

Question 5

What is a high dose of MTX?

Answer 5

Individual doses of > 1g / m2

Question 6

Why is oral MTX delivery rarely associated with toxicity?

Answer 6

Absorption of MTX is an active process so in an overdose saturation occurs and only a certain no. of receptors permit entry to cells

Question 7

What is the permeability of MTX like?

Answer 7

Low permeability (logP = 0.53)

More soluble in bloodstream in salt form; Log P -1.85

Question 8

What are the problems with sub-therapeutic doses of MTX?

Answer 8

Non therapeutic

Increased risks of resistance developing

Question 9

Why is prolonged exposure of MTX needed?

Answer 9

Only kills actively dividing cells

Question 10

What active ingredient is found in oral formulations of MTX?

Answer 10

Methotrexate sodium

More soluble in blood stream in salt form

Question 11

When is oral formulation of MTX used?

Answer 11

Arthritic conditions

Question 12

When are I.M MTX injections used?

Answer 12

In rheumatoid arthritis (lower doses than in anti-cancer)

Question 13

What are the benefits of MTX I.M injection?

Answer 13

Better absorption than by oral route (no saturation of receptors and well perfused)
Slower absorption and more prolonged exposure to drug than IV administration.

Question 14

Why are parenteral routes needed rather than oral routes in high doses of MTX?

Answer 14

Anticancer doses normally high, parenteral route needed because oral route is saturable - the F does not increase with increasing doses about a certain threshold

Question 15

Where are low dose oral MTX absorbed?

Answer 15

Mainly absorbed from the GI tract?

Question 16

Which route of administration is rapidly and completely absorbed?

Answer 16

Intramuscular

Question 17

What is ascitic fluid?

Answer 17

MTX penetrate ascitic fluid 
Ascitic fluid (abnormal) accumulation of fluid in the abdominal (peritoneal) cavity.

Question 18

What is the consequence of MTX penetrating ascitic fluid and effusions?

Answer 18

Can act as a deposit (poor control of distribution) and enhance toxicity

Question 19

What kind of clearance from plasma is shown by MTX?

Answer 19

Triphasic clearance

Question 20

How does MTX enter cells?

How does it stay there?

Answer 20

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.

Question 21

What are some of the factors that make MTX pharmacokinetics highly variable?

Answer 21

Affected by age, renal and hepatic function

Question 22

What is MTX solubility like?

Answer 22

Poor / limited lipid solubility; does not diffuse across lipid membranes (needs transporters).
Also, not transported into CSF after oral or IV administration.

Question 23

What is the main route of administration for MTX?

Answer 23

Renal - glomerular filtration, active tubular secretion.

Question 24

What is toxicity mostly dependent on?

Answer 24

Duration of exposure more than administered dose

The accumulation of polyglutamate form (metabolism slow)

Question 25

What are the practical issues associated with MTX?

Answer 25

MTX can bind to proteins; approx 50% bound, (unpredictable variation)
There is a variation between oral and IV early elimination rates.

Question 26

What does MTX interact with?

Answer 26

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

Question 27

What is a problem associated with high dose MTX and supersaturation?

Answer 27

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.

Question 28

What are the risk factors associated with MTX crystal formation in high dose administration?

Answer 28

Acid urine, volume depletion, renal impairment

Question 29

How can we minimise MTX nephrotoxicity?

Answer 29

Minimise with hydration and urinary alkalinisation

- sodium bicarbonate or acetazolamide

Question 30

What happens to F as oral dose increases?

Answer 30

Percentage F falls

Question 31

In the instance of MTX IV overdose what can be done?

Answer 31

Antidote folinic acid (Leucovorin) given intravenously
Timing is critical - efficacy drops rapidly with time after overdose
Need to maintain high hydration (avoid acidic urine)

Question 32

Does MTX cross the BBB?

Answer 32

In high dose MTX it does cross the BBB

- Danger of severe damage / death if incorrectly dosed

Question 33

How can resistance develop?

Answer 33

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.