Abstract
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.
Footnotes
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Send reprint requests to: Dr. R. Martino, Groupe de RMN Biomédicale, Laboratoire des IMRCP, Université Paul Sabatier, 118, route de Narbonne, 31062 Toulouse, France.
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This study was supported by grants from the Association pour la Recherche sur le Cancer (Grant 6635) and Ligue Nationale Française contre le Cancer (Comité des Hautes-Pyrénées). This study was presented in part at the 88th Annual Meeting of the American Association for Cancer Research (San Diego, CA, April 12–16, 1997).
- Abbreviations used are::
- CP
- cyclophosphamide
- CYP
- cytochrome P450
- OHCP
- 4-hydroxycyclophosphamide
- AldoCP
- aldophosphamide
- PM
- phosphoramide mustard
- KetoCP
- ketophosphamide
- CXCP
- carboxycyclophosphamide
- AlcoCP
- alcophosphamide
- DCCP
- dechloroethylcyclophosphamide
- NBP
- 4-(p-nitrobenzyl)pyridine
- NNM
- nor-nitrogen mustard
- DDCCP
- didechloroethylcyclophosphamide
- IF
- ifosfamide
- Cr(acac)3
- chromium(III) acetylacetonate
- MPA
- methylphosphonic acid
- 9-OdAP
- oxadiazaphosphacyclononane
- PAE1
- phosphoric acid ester 1
- PAE2
- phosphoric acid ester 2
- PAmA
- phosphoramidic acid
- DCPM
- dechloroethylphosphoramide mustard
- PAEAc
- phosphoric acid ester of 3-hydroxypropanoic acid
- PAEAm
- phosphoric acid ester of 3-hydroxypropanamide
- PAmAE1
- phosphoramidic acid ester 1
- 6-OAP
- oxazaphosphacyclohexane
- PAmAE2
- phosphoramidic acid ester 2
- RT
- repetition time
- Received September 30, 1997.
- Accepted January 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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