High impact information on C07646

• Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo [1].
• A key finding was the detection of a metabolite, most likely carboxyphosphamide, that is formed only by cytosols from cells expressing either class 3 or class 1 ALDH [2].
• Kinetic characterization of the catalysis of "activated" cyclophosphamide (4-hydroxycyclophosphamide/aldophosphamide) oxidation to carboxyphosphamide by mouse hepatic aldehyde dehydrogenases [3].
• ALDH-1-catalyzed oxidation of aldophosphamide (160 microM) to carboxyphosphamide occurred at a mean (+/- SD) rate of 5.0 +/- 1.4 atmol/min/rbc (red blood cell) [4].
• Phosphorus-31 nuclear magnetic resonance spectroscopy was used to evaluate the stability of carboxycyclophosphamide (CXCP) and carboxyifosfamide (CXIF) in human urine at pH 7.0 and 5.5 at 25 degrees, 8 degrees, -20 degrees, and -80 degrees C. At 25 degrees C and pH 7.0, CXCP and CXIF are relatively stable (approximately 10% degradation in 24 h) [5].

Biological context of C07646

• The biotransformation of CP was studied by the determination of the CP metabolites, nor-nitrogen mustard (NNM), 4-ketocyclophosphamide (KCP), and carboxyphosphamide (CAR) [6].

Anatomical context of C07646

• Carboxyphosphamide: NMR studies of its stability and cell membrane permeability [7].
• Fractional dose perfusion of U937 or K562 cells with 1.5 mmol/l 4-HO-CP/AP (generated from 4-HO2-CP) and 0.3 mmol/l mesna allowed for the observation of intracellular carboxyphosphamide (CBP); CBP was formed in higher concentrations in the CP-resistant K562 cells [8].

Analytical, diagnostic and therapeutic context of C07646

• However, during high-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P < .01) and in the formation clearance of carboxyphosphamide (7 v 12 mL/min; P < .05) and dechloroethylCP (3.2 v 4.2 mL/min; P < .05), whereas metabolic clearance to ketoCP remained unchanged (1.3 v 1.2 mL/min) [9].

References