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 anc 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)2Cl(SG)] and cis-([Pt(NH3)2Cl]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/m2 to patients) preceded by a GSH intravenous administration (200 mg/kg to rats as a bolus and 1.5 g/m2 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.
Bernareggi
A
A
Boehringer Mannheim Italia SpA, Research Center, Monza (MI), Italy.
Torti
L
L
Facino
R M
RM
Carini
M
M
Depta
G
G
Casetta
B
B
Farrell
N
N
Spadacini
S
S
Ceserani
R
R
Tognella
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002021:Buffers; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D009944:Organoplatinum Compounds / Q000097:blood*; D010710:Phosphates / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013054:Spectrophotometry, Atomic; D013056:Spectrophotometry, Ultraviolet; D013736:Testicular Neoplasms / Q000097:blood* / Q000188:drug therapy
D000970:Antineoplastic Agents; D002021:Buffers; D009944:Organoplatinum Compounds; D010710:Phosphates; C096772:mu-S-glutathionyl-bis(cis-diamminechloroplatinum(II)); C096771:diamminechloro(glutathionato-S)platinum(II); D005978:Glutathione; D002945:Cisplatin; C018279:sodium phosphate