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  • Title: Stereoselective pharmacokinetics of L-buthionine SR-sulfoximine in patients with cancer.
    Author: Lacreta FP, Brennan JM, Hamilton TC, Ozols RF, O'Dwyer PJ.
    Journal: Drug Metab Dispos; 1994; 22(6):835-42. PubMed ID: 7895599.
    Abstract:
    Buthionine sulfoximine (BSO) is an inhibitor of glutathione synthesis that can deplete intracellular glutathione and reverse resistance to platinating and alkylating agents in vitro and in vivo. We are performing a phase I study of BSO in combination with melphalan. The BSO used in this study was provided by the National Cancer Institute and is a mixture of the R- and S-diastereomers of L-BSO. We developed a reversed-phase HPLC assay to quantitate levels of the R- and S-BSO isomers in plasma and urine. The pharmacokinetics of BSO was determined in 11 patients: 3 patients at 5 g/m2, 4 patients at 7.5 g/m2, and 4 patients at 10.5 g/m2. Plots of plasma area under the concentration-time curve vs. dose for both R-BSO (r2 = 0.798) and S-BSO (r2 = 0.752) are linear, indicating linear pharmacokinetics in this dose range. However, the individual BSO isomers exhibit stereoselective disposition and elimination. Values for steady-state volume of distribution and renal clearance were similar for both isomers, but total clearance, nonrenal clearance, and half-life were approximately 25% different, with the R-(inactive) isomer being eliminated faster (higher clearance and shorter half-life) than the S- (active) isomer. Using a paired t test, we found that the pharmacokinetic parameters, total clearance, nonrenal clearance, and half-life for R-BSO were significantly different (p < 0.05) from those for S-BSO. Renal clearance of both S- and R-isomers approximated glomerular filtration rate and accounted for 64% of S-BSO total clearance and 56% of R-BSO total clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
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