Urinary excretion of cyclophosphamide in humans, determined by phosphorus-31 nuclear magnetic resonance spectroscopy.
Phosphorus-31 NMR spectroscopy was used to analyze urine samples from patients treated with cyclophosphamide (CP) on 2 consecutive days. CP and all of its known phosphorylated metabolites except the tautomeric pair 4-hydroxycyclophosphamide/aldophosphamide, i.e. carboxycyclophosphamide (CXCP), dechloroethylcyclophosphamide (DCCP), alcophosphamide, ketophosphamide, and phosphoramide mustard (PM), were determined. Several other signals corresponding to unknown CP-related compounds were observed. Seven of them were identified; all were hydrolysis products of CP or its metabolites (one from CP, two from CXCP, three from DCCP, and one from PM). Twenty-four-hour urinary excretion of unmetabolized CP was not significantly different on the first (17% of the daily administered dose) and second (16%) days of treatment. The amounts of phosphorylated metabolites excreted in 24-hr urine samples were much higher after the second CP dose (37%) than after the first (20%), suggesting autoinduction of CP metabolism. CXCP and its two degradation products (accounting for 7-10% of CXCP) were by far the major metabolites (11.5 and 23% after the first and second doses, respectively). DCCP plus its degradation products and alcophosphamide each represented 2-3% on the first day of treatment and 5% on the second day of treatment. Levels of PM and its degradation products were extremely low (0.3 and 0.6% after the first and second CP doses, respectively), as were those of ketophosphamide (0.4 and 0.6% on the first and second days of treatment, respectively). We noted only modest interpatient variation in excreted levels of CP and all of its metabolites.
Joqueviel
C
C
Biomedical NMR Group, Interactions Moleculaires et Reactivite Chinique et Photochinique Laboratory, Université Paul Sabatier, Toulouse, France.
Martino
R
R
Gilard
V
V
Malet-Martino
M
M
Canal
P
P
Niemeyer
U
U
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D003520:Cyclophosphamide / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D010759:Phosphorus Isotopes
D018906:Antineoplastic Agents, Alkylating; D010759:Phosphorus Isotopes; D003520:Cyclophosphamide