Pharmacokinetics and metabolism of the antitumor agent sulfamic acid 1,7-heptanediyl ester (sulfamic acid diester) in the mouse and beagle dog.
The pharmacokinetics and metabolism of sulfamic acid diester were studied in the beagle dog and mouse. Elimination of sulfamic acid diester from the plasma and whole blood following i.v. administration at a dose of 193 mg/m2 was best approximated by a three-compartment model in both species. The compound was relatively rapidly cleared from the plasma, with a plasma beta half-life of 2.3 h and 0.9 h and a gamma half-life of 16 h and 3 h in the dog and the mouse, respectively. Sulfamic acid diester was taken up by blood cells and only slowly eliminated with a whole blood gamma half-life of 42 h in the dog and 32 h in the mouse. When sulfamic acid diester was infused i.v. to mice at 15 mg/kg over 8 h, the clearance for the parent drug was 13.2 ml/min kg from the plasma and 3.3 ml/min kg from the whole blood. Urine collected from mouse and dog contained the parent drug and three metabolic/breakdown products, namely, sulfamic acid 1,7-heptanemonoyl ester, sulfamic acid 3-hydroxyl-1,7-heptanediyl ester, and an unidentified product. Excretion of unchanged drug and products in mouse urine over 8 h accounted for less than 16% of the dose of sulfamic acid diester. Sulfamic acid diester did not react with glutathione in buffer, whole blood, or 100,000 g rat liver cytosol.