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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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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 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.
Notes
English Article PV163 DRUG METAB DISPOSITION