MTX is well absorbed.
After absorption, approximately 10% of MTX is converted to its major metabolite 7-
Hydroxy-Methotrexate (7-OH-MTX). The hydroxylation
process takes place in the liver via hepatic aldehyde oxidase and results in a much less
active form of MTX. 7-OH-MTX is less water soluble as compared to MTX and may
contribute to the renal toxicity frequently seen after high doses of MTX. (Tian and Cronstein, 2007) thus causing the side effect of nephrotoxicity and also may inhibit any further uptake of MTX by cancer cells.
My question is WHY 7-OH MTX is less soluble than MTX ? or what makes it less soluble?
No hard data, but a guess.
I would guess that the hydroxyl moiety (slightly acidic) in the 7-position hydrogen bonds to the anilinic nitrogen of the pendant p-substituted phenyl group and thus attenuates flexibility in the molecule in comparison to the parent compound. This will affect crystallinity and solubility.
Another possibility, based only on my experiences with other petridine rings, is that when you get 7-OH-MTX the hydroxy group will tautomerize to make the internal lactam (amide)
This results in the bottom face of the ring having an acceptor-donor-acceptor array of hydrogen bonding(O, NH, N), while the left face of the ring has a donor-acceptor-donor hydrogen bond array (NH, N, NH)
This leads to extremely strong solute-solute interactions which are too strong to be compensated by solvent interactions
This is the same reason why folate is less soluble than methotrexate
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