No abstract

The alkylating activity in the urine was measured in patients receiving a new antineoplastic cyclophosphomide analog, isophosphamide (IP), at doses of 2,900 to 5,000 mg per square meter body surface area (BSA) and compared with that of patients receiving 1,100 mg per square meter of cyclophosphamide (CP). Total excretion of alkylating activity after CP (1,l00 mg per square meter) lay between values for the 3,800 mg per square meter dose and the 5,000 mg per square meter dose of IP. The concentration of urinary alkylating activity was higher in patients who developed cystitis than in those who did not. Alkylating activity in the urine was unaltered by acetylcysteine bladder washout. Plasma alkylating activity was more persistent after 5,000 mg per square meter IP than after 1,100 mg per square meter CPo After [HC] IP 5,000 mg per square meter, the plasma half-life was 13.79 hours, and the urinary recovery of radioactivity was 81.6%, of which 61.6% was unchanged drug. These values differ markedly from those published for CPo IP penetrated the blood-brain barrier, but its metabolites did not. The greater propensity of IP than of CP to cause cystitis at apprOXimately equitoxic doses may be related to larger amounts of alkylating activity in urine of patients receiving [P. The greater dose of IP than of CP required to produce the same alkylating activity in urine correlates well with the differences in Km of the two drugs in an isolated microsomal enzyme system in vitro previously reported.

A reverse phase high performance liquid chromatographic (HPLC) assay for the quantitative determination of cyanuric acid (CA) in urine and water is described. For purification, samples are passed through a pre-activated reverse phase C18 column. The effluent is dried by lyophilization, and the residue is reconstituted in hexane-washed water and then passed through a prewashed Dowex-1 column. The effluent is again dried by lyophilization, and the dry residue is extracted with hot dioxane. The solution is cooled to ambient temperature and centrifuged. The supernatant liquid is removed, dried under a nitrogen steam, and dissolved in water for final extraction by reverse phase chromatography. This effluent is dried, dissolved in the sodium phosphate monohydrate in methanol (pH 7.0) mobile phase, and injected into a pre-equilibrated chromatographic system. An external standard is used for quantification by peak height comparison. A sample of HPLC column effluent is collected, dried, dissolved in methanol, and used for mass spectrometric confirmation by a solid probe insert procedure. Average combined recovery determined at 1.0, 5.0 and 10.0 μg CA/mL is 103 ± 3% with an average coefficient of variation of 8.6%. Standard deviations for the 3 concentration levels are 0.04, 0.58, and 0.76, respectively, with average precisions of 4.28, 10.92, and 7.61%. The limits of detection are approximately 0.05 μg/mL for urine and 0.1 μg/mL for swimming pool water. Recorder response to CA is linear over the concentration range 1-10 μg/mL.

Nine patients were studied with tritium-labeled EPEG, a new epipodophyllotoxin antineoplastic agent. Four patients received 220 and 5 received 290 mg/sq m body surface area intravenously in 500 ml in 1 hr. Postinfusion plasma decay was biphasic with mean values for the parameters at 220 mg/sq m, A, 25.8 mug/ml; B, 3.35 mug/ml: alpha, 0.50 hr-1; beta, 0.074 hr-1, and mean values at 290 mg/sq. m, A, 33.7 mug/ml; B, 4.35 mug/ml; alpha, 0.36 hr-1; beta, 0.066 hr-1. Mean volume of distribution was 32.07% of body weight. Urinary recovery was 43.5%, of which 66.8% was unchanged drug. Penetration of drug into the cerebrospinal fluid was poor. The results indicate that both renal excretion and metabolism are important for elimination of the drug.

A multicompartment pharmacokinetic model for ifosfamide has been employed using a system of first-order differential equations, which includes a term for metabolism according to Michaelis-Menten kinetics in order to describe the distribution and elimination parameters of ifosfamide in man. The model satisfactorily accounts for all the administered drug. The pseudometabolic rate constant for ifosfamide in man is found to be less than 20 percent of that reported for cyclophosphamide in man, in agreement with the more extensive metabolism of cyclophosphamide than ifosfamide. A number of the pharmacokinetic parameters for ifosfamide differ substantially from those reported for cyclophosphamide. The volume of distribution for ifosfamide metabolites was found to be approximately equal to the plasma space volume. The central compartment volume for intact ifosfamide is slightly larger than for cyclophosphamide and includes the easily diffusible extravascular space of the body and suggests lack of protein binding. The renal clearance of ifosfamide is low and about twice that of cyclophosphamide. The model indicates that only a small fraction of the total metabolites distribute into the peripheral compartment and suggests that multiple doses of the drug may be useful.