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Lacreta FP , Brennan JM , Hamilton TC , Ozols RF , Odwyer PJ
Stereoselective Pharmacokinetics of L-Buthionine Sr-Sulfoximine in Patients with Cancer
Drug Metabolism and Disposition. 1994 Nov-Dec;22(6) :835-842
PMID: ISI:A1994PV16300005   
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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 BSC was determined in 11 patients: 3 patients at 5 g/m(2), 4 patients at 7.5 g/m(2), and 4 patients at 10.5 g/m(2). Plots of plasma area under the concentration-time curve vs. dose for both R-BSC (r(2) = 0.798) and S-BSO (r(2) = 0.752) are linear, indicating linear pharmacokinetics in this dose range. However, the individual BSC 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 similar to 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. The mean ratio of renal clearance to creatinine clearance was 1.02 for S-BSO and 1.10 for R-BSO. There was a statistically significant linear relationship between R-BSO total clearance and creatinine clearance (r(2) = 0.503) and S- BSO total clearance and creatinine clearance (r(2) = 0.624). Nonrenal clearance was significantly greater for R-BSO compared with S-BSO, suggesting a metabolic component for BSO elimination that has greater activity for R-BSO. Because S-BSO is more potent and has a different mechanism of glutathione inhibition than R-BSO, understanding the pharmacokinetics of the individual isomers is important for the optimal clinical use of this drug.