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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat.

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/, 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)[1]


  1. Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat. Hong, P.S., Srigritsanapol, A., Chan, K.K. Drug Metab. Dispos. (1991) [Pubmed]
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