Stereoselective pharmacokinetics of L-buthionine SR-sulfoximine in patients with cancer.
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)
Lacreta
F P
FP
Department of Pharmacology, Fox Chase Cancer Center. Philadelphia, PA 19111.
Brennan
J M
JM
Hamilton
T C
TC
Ozols
R F
RF
O'Dwyer
P J
PJ
D000368:Aged; D019328:Buthionine Sulfoximine; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D013237:Stereoisomerism
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine