35144-64-0Relevant articles and documents
31P Nuclear Magnetic Resonanse Spectroscopic Observation of the Intracellular Transformations of Oncostatic Cyclophosphamide Metabolites
Boyd, Victoria L.,Robbins, Joan D.,Egan, William,Ludeman, Susan M.
, p. 1206 - 1210 (1986)
(31)P NMR spectroscopy was used to directly monitor, for the first time, the intracellular chemistry of the ultimate active metabolite of cyclophosphamide, namely, phosphoramide mustard.These NMR studies utilized a human histiocytic lymphoma cell line (U937), embedded in agarose gel threads, and perfused with medium containing synthetically derived metabolites (4-hydroxycyclophosphamide (2), aldophosphamide (3), and phosphoramide mustard (4)).Metabolites 2 or 3 or both readily crossed the cell membrane; in contrast, the membrane was relatively impermeable to 4.Intracellular concentrations of 4 could, therefore, be attributed primarily to the intracellular fragmentation of 3.Signals suggestive of either carboxyphosphamide or 4-ketophosphamide were not detected.Spectral data were used to calculate a rate constant of (5.4 +/- 0.3) * 10-3 min-1 for the intracellular disappearance of 4 at 23 deg C.The intracellular pH was determined to be 7.1 from the chemical shift of the internal inorganic phosphate signal.
In situ preparation and fate of cis-4-hydroxycyclophosphamide and aldophosphamide: 1H and 31P NMR evidence for equilibration of cis- and trans-4-hydroxycyclophosphamide with aldophosphamide and its hydrate in aqueous solution
Borch,Hoye,Swanson
, p. 490 - 494 (2007/10/02)
cis-4-Hydroxycyclophosphamide (2) and aldophosphamide (4) were generated in aqueous phosphate or cacodylate buffer by dimethyl sulfide reduction of cis-4-hydroperoxycyclophosphamide and by sodium periodate cleavage of 3,4-dihydroxybutyl N,N-bis(2-chloroethyl)phosphorodiamate, respectively; the reactions of 2 and 4 were examined by 1H and 31P NMR. Within 30-60 min (pH or pD 7.0, 25 °C) the same pseudoequilibrium mixture was established in both reactions, with cis- and trans-4-hydroxycyclophosphamide (2 and 3), aldophosphamide (4), and its hydrate (5) present in the approximate ratio of 4:2:0.3:1. Structures of the intermediates were assigned unambiguously based upon analysis of the chemical shifts and coupling constants in the proton spectra determined in D2O buffers, and the 31P assignments followed by correlation of component ratios at equilibrium. Free energy differences of 0.4, 0.4, and 0.7 kcal/mol at 25 °C were estimated between 2, 3, 5, and 4, respectively, with 2 being the most stable. The aldehyde 4 reacted most rapidly with water to give hydrate 5; cyclization of 4 to 3 occurred faster than to 2. Compound 5 is formed much faster than 3 from the diol cleavage, but 5 and 3 are produced at comparable rates from 2, suggesting that conversion of 2 to 3 can proceed by a mechanism other than ring opening. The rate of equilibration appears to be independent of buffer structure, indicating that bifunctional catalysis is not important in the ring-opening reaction. β-Elimination from 4 is rate limiting for the production of acrolein, and the rate for phosphate is 2- to 3-fold faster than for cacodylate under identical conditions. These results provide the first definitive evidence for the stability of the elusive aldehyde 4 in aqueous solution and for the existence of a preequilibrium among 2-5 prior to rate-limiting expulsion of phosphoramide mustard from 4.
Effect of damaged liver parenchyma, renal insufficiency and hemodialysis on the pharmacokinetics of cyclophosphamide and its activated metabolites
Wagner,Heydrich,Bartels,Hohorst
, p. 1588 - 1592 (2007/10/02)
Patients with impaired liver function have a reduced biotransformation rate of the cytostatic agent cyclophosphamide. With pathologically reduced serum cholinesterase activity the half-life of the drug increases from normally 4.3 h to 6.7 h. These patients show significantly lower peak levels of activated cyclophosphamide (4-hydroxy-cyclophosphamide + aldophosphamide). Because of the low renal clearance of cyclophosphamide (16 ml/min) and equally low renal excretion of activated cyclophosphamide amounting to only 1% of the applied dose more than 80% of the drug is still metabolized and the area under the curve of activated cyclophosphamide (cXt) remains relatively constant. No change in the pharmacokinetics of cyclophosphamide and its activated metabolite is observed in an anuric patient. However, an accumulation of toxic, directly alkylating metabolites with a fourfold alkylation rate of plasma proteins is found in this case. Hemodialysis sufficiently eliminated the toxic alkylating metabolites without a measurable influence on the pharmacokinetics of activated cyclophosphamide.
