Determination of glyciphosphoramide and its metabolite in plasma and the pharmacokinetics in rats after oral administration
Wang, W.J.; Bai, J.Y.; Zhu, X.Y.
Yao Xue Xue Bao 28(10): 738-743
1993
ISSN/ISBN: 0513-4870 PMID: 8009985 Document Number: 408873
Glyciphosphoramide (GPA) is one of the anticancer agents belonging to the group of phosphoramide mustard. It has apparent antitumor effects in some animal models and in clinical trials against breast cancer, lymphosarcoma, uterocervical cancer and cancerous ulcer with good results. In this paper, the determination procedure of GPA and its metabolite using nitrobenzylpyridine (NBP) method is reported. The absorbance of the coloured products from the reaction of hydrolyzed or metabolized GPA with NBP was measured at 570 nm and 564 nm, respectively. The linearity of the reaction for GPA and its metabolite was established over the range of 6.25 apprx 100 mu-g/ml water or plasma. The plasma of rats and mice was found to be able to metabolize GPA to form alkylating agent (s) which react with NBP, but that of rabbits cannot. The plasma concentration - time curve of metabolite obtained after oral administration of GPA (100 mg/kg) in rats was shown to fit a two compartment open model with the following parameters: T-1/2-beta = 44.5 min, T-1/2-alpha = 3.16 min, T-1/2Ka = 2.14 min, T-1/2 Km = 0.0644 min, T-max = 7.57 min, C-max = 55.8 mu-g/ml, AUC = 2827.39 mu-g/ml cntdot min, K-21 = 0.09663/min, K-10 = 0.03535/min, K-12 = 0.1030/min, Vc = 1.00 L/kg, Vd = 2.07 L/kg, CLt = 2.12 L/h. Kidney was found to be the main organ for GPA metabolite elimination. About one fourth of the given dose was excreted in urine within 24 h with the main portion excreted in the first 2 h.