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Phenotypically Deficient Urinary Elimination of Carboxyphosphamide after Cyclophosphamide Administration to Cancer Patients¹

Department of Pharmacology and Toxicology, St. Mary's Hospital Medical School [A. F. A. H., J. R. I], and Department of Radiotherapy, St. Mary's Hospital [C. E. A. C.], London, United Kingdom

The 0-24-h urinary metabolic profile of cyclophosphamide was investigated in a series of 14 patients with various malignancies receiving combination chemotherapy including i.v. cyclophosphamide. This was accomplished using combined thin-layer chromatography-photography-densitometry, which can quantitate cyclophosphamide and its four principal urinary metabolites (4-ketocyclophosphamide, nor-nitrogen mustard, carboxyphosphamide, and phosphoramide mustard). Recovery of drug-related metabolites was 36.5 ± 17.8% (SD) dose, the most abundant metabolites being phosphoramide mustard (18.5 ± 16.1% dose) and unchanged cyclophosphamide (12.7 ± 9.3% dose). The most variable metabolite was carboxyphosphamide, with five patients excreting 0.3% dose or less. These patients were termed low carboxylators (LC) and could be distinguished from high carboxylators (HC) by a carboxylation index (relative percentage as carboxyphosphamide multiplied by 10). Mean carboxylation indices for the LC and HC phenotypes were 3.4 ± 2.6 and 151 ± 115, respectively. There were no associations between patient age, sex, body weight, tumor type, or concomitant drug therapy and carboxylation phenotype. Neither 4-ketocyclophosphamide nor nornitrogen mustard excretion differed between LC and HC phenotypes; however, HC patients had a greater excretion of cyclophosphamide (46.4 ± 15.5 relative percentage) than LC patients (19.4 ± 12.6%). The DNA cross-linking cytotoxic metabolite phosphoramide mustard was elevated more than 2-fold in the LC (76.5 ± 13.9%) compared with the HC (33.0 ± 12.2%) phenotype. It is concluded that these data represent the first evidence of a defect in cyclophosphamide metabolism, and it is proposed that this arises from a hitherto unrecognized aldehyde dehydrogenase genotype.

¹ Supported by grants from the Cancer Research Campaign (UK) and The Wellcome Trust.

² Supported by The British Council and Yarmouk University, Jordan. Present address: Faculty of Medicine, Jordan University of Science and Technology, Erbid, Jordan.

³ Wellcome Trust Senior Lecture. To whom requests for reprints should be addressed.

Received 2/10/88. Revised 6/15/88. Accepted 6/21/88.

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