Pharmacokinetics and metabolism of the antitumor agent sulfamic acid 1,7-heptanediyl ester (sulfamic acid diester) in the mouse and beagle dog
Tóm tắt
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.
Tài liệu tham khảo
Alley MC, Powis G, Appel PL, Kooistra KL, Lieber MM (1984) Activation and inactivation of cancer chemotherapeutic agents by rat hepatocytes cocultured with human tumor cell lines. Cancer Res 44:549
Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248
Brodfuehrer JI, Powis G (1988) Chromatographic assay for the new antitumor agent sulfamic acid diester (NSC 329680) and its stability in buffer, blood and plasma. J Chromatogr (in press)
Ehrsson H, Hassan M (1984) Binding of busulfan to plasma proteins and blood cells. J Pharm Pharmacol 36:694
Ernster L, Siekevitz P, Palade PE (1962) Enzyme-structure relationships of the endoplasmic reticulum of rat liver. J Cell Biol 15:541
Feit PW, Rastrup-Andersen N (1973) 4-Methanesulfonyloxybutanol: hydrolysis of busulfan. J Pharm Sci 62:1007
Habig WH, Jakoby WB (1981) Glutathione S-transferases (rat and human). In: Jakoby WB (ed) Methods in enzymology, vol 77. Academic Press, New York, p 218
Hassan M, Ehrsson H (1986 a) Degradation of busulfan in aqueous solution. J Pharm Biomed Anal 4:95
Hassan M, Ehrsson H (1986 b) Urinary metabolites of busulfan in the rat. Drug Metab Dispos 15:399
Hassan M, Ehrsson H (1987) Metabolism of 14C-busulfan in isolated perfused rat liver. Eur J Drug Metab Pharmacokinet 12:71
Metzler CM, Elfring G, McEwen AJ (1974) A package of computer programs for pharmacokinetic modeling. Biometrics 30:562
National Cancer Institute Preclinical Brochure (1986) Sulfamic acid diesters (NSC 329680). National Cancer Institute, Bethesda, Md
Paborji M, Waugh WN, Stella VJ (1986) Mechanistic investigation of the degradation of sulfamic acid 1,7-heptanediyl ester, an experimental cytotoxic agent, in water and 18oxygen-enriched water. J Pharm Sci 76:161
Powis G, Hodnett EM, Santone KS, Lee-See K, Melder DC (1987) Role of metabolism and oxidation-reduction cycling in the cytotoxicity of antitumor quinoneimines and quinonediimines. Cancer Res 47:2363
Wagner JG (1976) Pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. J Pharm Biopharm 4: 443