A. FOLIC ACID ANALOGUES: METHOTREXATE, PEMETREXED, PRALATREXATE
Pharmacokinetics
- use specific transporters to enter cells (see discussion in Folate/Vitamin B12 lecture)
- – some types of cancer cells:
- overexpress the folate receptor → selective toxicity
- underexpress the reduced folate carrier → resistance
- – some types of cancer cells:
METHOTREXATE
- administration can be:
- oral (low doses only) – readily absorbed from GI tract, high bioavailability
- IV (high doses)
- intrathecal to overcome the fact that MTX is ionized and crosses the blood brain barrier poorly
- overdose is a common complication with this route of administration
- 90% excreted unchanged in urine (no significant metabolism) via a combination of glomerular filtration and active tubular secretion
- changes in renal excretion can delay elimination and lead to severe myelosuppresion (the dose limiting toxicity)
- must administer with bicarbonate to maintain urine pH above 6.5
- significant pharmacokinetic interactions with drugs that alter kidney function by:
- decreasing renal blood flow (e.g. NSAIDS)
- causing nephrotoxity (e.g. CISPLATIN)
- being weak acids (e.g. aspirin)