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Pharmacokinetics of Buthionine Sulfoximine (NSC 326231) and Its Effect on Melphalan-induced Toxicity in Mice¹

Toxicology Branch, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892 [A. C. S., C. K. G.]; Springborn Life Sciences, Inc., Spencerville, Ohio 45887 [J. T. F. L.]; and Battelle Columbus Division, Columbus, Ohio 43201 [J. G. P., M. G. W.]

Intravenous doses of buthionine sulfoximine (BSO, NSC 326231), an inhibitor of glutathione synthesis, were eliminated rapidly from mouse plasma in a biexponential manner. The initial phase of the plasma concentration versus time curve had a half-life of 4.9 min and accounted for 94% of the total area under the curve. The half-life of the terminal phase of the curve was 36.7 min and the area accounted for only 6% of the total area under the curve. Plasma clearance of BSO was 28.1 ml/min/kg and the steady state volume of distribution was 280 ml/kg. The oral bioavailability of BSO, based on plasma BSO levels, was extremely low. However, comparable glutathione depletion was apparent after i.v. and p.o. doses of BSO, suggesting a rapid tissue uptake and/or metabolism of BSO. Therefore, due to the rapid elimination of BSO from mouse plasma, plasma drug levels do not directly correlate with BSO-induced tissue glutathione depletion. Administration of multiple i.v. doses of BSO to male and female mice resulted in a marked 88% depletion of liver glutathione at doses of 400–1600 mg/kg/dose. Toxicity of i.v. administered BSO was limited to a transient depression of peripheral WBC levels in female mice given six doses of 1600 mg/kg. Multiple i.v. doses of BSO of up to 800 mg/kg/dose (every 4 h for a total of six doses) did not alter the toxicity of i.v. administered melphalan. However, multiple doses of 1600 mg/kg/dose of BSO did potentiate histopathological evidence of melphalan-induced bone marrow toxicity in 30% of the mice and, additionally, the combination of BSO and melphalan produced renal tubular necrosis in 80% of the male mice. The potentiation of melphalaninduced toxicity did not appear to be related to GSH depletion, since a quantitatively similar amount of GSH depletion occurred at lower doses of BSO without any increase in melphalan toxicity.

¹ This work was supported by Contracts NO1-CM-17365 and NO1-CM-87256 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Toxicology Branch, DTP, DCT, National Cancer Institute, Executive Plaza North, Room 843, Bethesda, MD 20892.

Received 2/22/89. Revised 6/ 2/89. Accepted 6/23/89.