title: Phenotypically deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients.
abstract: 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 nor-nitrogen 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.
authors.affiliation: Department of Pharmacology and Toxicology, St. Mary's Hospital Medical School, London, United Kingdom.
authors.forename: A H
authors.initials: AH
authors.lastname: Hadidi
authors.forename: C E
authors.initials: CE
authors.lastname: Coulter
authors.forename: J R
authors.initials: JR
authors.lastname: Idle
mesh_terms: D000328:Adult; D000368:Aged; D002855:Chromatography, Thin Layer; D003520:Cyclophosphamide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000652:urine*; D010641:Phenotype; D010752:Phosphoramide Mustards / Q000652:urine*
chemical_list: D010752:Phosphoramide Mustards; D003520:Cyclophosphamide; C000028:carboxyphosphamide