title: Stereoselective pharmacokinetics of L-buthionine SR-sulfoximine in patients with cancer.
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)
authors.affiliation: Department of Pharmacology, Fox Chase Cancer Center. Philadelphia, PA 19111.
authors.forename: F P
authors.initials: FP
authors.lastname: Lacreta
authors.forename: J M
authors.initials: JM
authors.lastname: Brennan
authors.forename: T C
authors.initials: TC
authors.lastname: Hamilton
authors.forename: R F
authors.initials: RF
authors.lastname: Ozols
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: 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
chemical_list: D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine