Pharmacologic studies on the dibutyl and ?-monobutyl esters of methotrexate in the rhesus monkey

Abstract

The pharmacokinetics and metabolism of dibutyl methotrexate (DBMTX) and gamma-monobutyl methotrexate (gamma-MBMTX) were studied in Rhesus monkeys. When a bolus IV dose of either [3H]DBMTX or [3H] gamma-MBMTX was given, the principal species in serum for up to 1 h was the monoester, with MTX accounting for less than 10% of the total radioactivity. Products other than gamma-MBMTX and MTX were formed in substantial amounts with DBMTX, but not with gamma-MBMTX. Total radioactivity recovered in the bile 5 h after [3H]DBMTX injection accounted for 32% of the administered dose, indicating high hepatic extraction for this lipophilic compound. Serum and CSF levels of unchanged gamma-MBMTX, as well as of MTX arising via esterase cleavage, were measured by HPLC after IV infusion of gamma-MBMTX (10 g/m2). Efflux of monoester from CSF was slower than disappearance from serum. However, gamma-MBMTX levels in CSF were no higher than could be attained by infusing MTX itself at the same dose rate. While CSF/serum ratios were ca. 10-fold higher for gamma-MBMTX than for MTX, this difference could be explained on the basis of the very different affinities of the two compounds for serum proteins. HPLC analysis of serum processed by methanol precipitation as opposed to ultrafiltration of the proteins showed gamma-MBMTX to be greater than 99% bound, whereas for MTX this value was 50% or less. When gamma-MBMTX and MTX levels measured after ultrafiltration were corrected for this difference in serum protein binding the total amount of the two drugs in serum became almost equivalent.

Development of methotrexate resistance in a human squamous cell carcinoma of the head and neck in culture.

“…Experimental studies using cells that are highly resistant to MTX are of biochemical interest but do not necessarily yield information relevant to the clin- (18). Increased enzyme production per gene has not been observed in S180 murine sarcoma (30) Our finding that MTX-resistant SCC15 cells are either not cross-resistant or only partly cross-resistant to nBu2MTX (26,37,38) and y-tBuMTX (27) This investigation was supported in part by National Cancer Institute Grants CA19589 and CA25394. Support for J.J. was provided in part by a fellowship from National Cancer Institute of Canada.…”

Highly regioselective 6-exo-dig iodo/bromo cyclizations of functionalized 5-amino propargyl pyrimidinones: an efficient synthesis of functionalized pteridines

“…2–4 Moreover, a number of prevalent diseases including inflammatory disorders, autoimmune processes, neurological diseases, and birth defects have been attributed to the problems in the synthesis, nutritional availability, and/or metabolism of these compounds. 3–14 Functionalized pteridines have also been explored for the treatment of fibroproliferative disorders, hepatitis C, 15,16 and vascular disorders, etc. 12,17–21…”

“…[2][3][4] Moreover, a number of prevalent diseases including inammatory disorders, autoimmune processes, neurological diseases, and birth defects have been attributed to the problems in the synthesis, nutritional availability, and/or metabolism of these compounds. [3][4][5][6][7][8][9][10][11][12][13][14] Functionalized pteridines have also been explored for the treatment of broproliferative disorders, hepatitis C, 15,16 and vascular disorders, etc. 12,[17][18][19][20][21] A group of heterocyclic compounds known as pteridine, pyrazino [2,3-d] pyrimidines are composed up of condensed pyrimidine/pyrimidinone and pyrazine rings.…”