CHARACTERIZATION OF CISPLATIN-GLUTATHIONE ADDUCTS BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY - EVIDENCE FOR THEIR FORMATION IN-VITRO BUT NOT IN-VIVO AFTER CONCOMITANT ADMINISTRATION OF CISPLATIN AND GLUTATHIONE TO RATS AND CANCER-PATIENTS

After incubation of equimolar amounts of cisplatin (CDDP) and glutathione (GSH) in phosphate buffer pH 7.4 at 37 degrees C, we detected two CDDP-GSH adducts whose structures, characterized by LC-MS, corresponded to cis-[Pt(NH3)(2)Cl(SG)] and cis-{[Pt(NH3)(2)Cl](2)(mu-SG)}(+). The latter is a new CDDP-GSH adduct, which was postulated but never structurally characterized so far. Rats and patients were given a 15-min intravenous infusion of CDDP (10 mg/kg to rats and 25 mg/m(2) to patients) preceded by a GSH intravenous administration (200 mg/kg to rats as a bolus and 1.5 g/m(2) to patients as a 15-min infusion). After the administrations, CDDP-GSH adducts were absent in rat and human plasma ultrafiltrates. The discrepancy between in vitro and in vivo findings can be explained based on pharmacokinetic considerations.