title: Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat.
abstract: Pharmacokinetics of 4-hydroxycyclophosphamide (4-OHCP), the major active microsomal metabolite of cyclophosphamide (CP), were investigated in the Sprague-Dawley rat following separate iv bolus administrations of CP, synthetic 4-OHCP, and their combination. CP, 4-OHCP, and other metabolites such as phosphoramide mustard, alcophosphamide, and 3-(2-chloroethyl)-1,3-oxazolidin-2-one in rat plasma were simultaneously analyzed using GC/MS and stable isotope dilution techniques. Following iv administrations of 4-OHCP to rats at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg, phosphoramide mustard was found to be the major circulating metabolite followed by alcophosphamide and 3-(2-chloroethyl)-1,3-oxazolidin-2-one. No appreciable amount of nor-nitrogen mustard was detected in circulation. The mean excretion of unchanged 4-OHCP in two rats was 4.1 +/- 0.2% of the administered dose in 24-hr urine. Plasma concentration-time profiles of 4-OHCP declined monoexponentially with a mean half-life and total plasma clearance values of 8.1 min and 81.2 ml/min.kg, respectively. No dose-dependent kinetics were apparent between the 10 and 40 mg/kg doses used. The short half-life of 4-OHCP may be due partly to its degradation in plasma, which was found to be a first-order process in vitro with a half-life of 5.2 min. On the other hand, when CP was administrated to eight separate rats at 20 mg/kg each, the mean apparent elimination half-life for the derived 4-OHCP was 55.4 min as compared to 58.2 min, the mean elimination half-life for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: School of Pharmacy, University of Southern California, Los Angeles 90033.
authors.forename: P S
authors.initials: PS
authors.lastname: Hong
authors.forename: A
authors.initials: A
authors.lastname: Srigritsanapol
authors.forename: K K
authors.initials: KK
authors.lastname: Chan
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D008297:Male; D010752:Phosphoramide Mustards / Q000097:blood / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D010752:Phosphoramide Mustards; C012358:4-hydroxycyclophosphamide; C006446:aldophosphamide; D003520:Cyclophosphamide