Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin.
The kinetics of platinum (Pt) was studied in 12 patients suffering from non-small-cell lung cancer or pleural mesothelioma. Each subject received an infusion of cisplatin (CDDP, 80 mg/m2), and six patients were pretreated with glutathione (GSH, 2.5 g given i.v.) at 15 min prior to the cisplatin infusion. After a 3- to 4-week interval, all patients were given a second course of treatment on the same schedule. A biexponential model was fitted to plasma concentrations of total and ultrafilterable Pt. The excretion of Pt in urine was evaluated during the first 48 h after the CDDP infusion. Following the administration of CDDP alone or with GSH pretreatment, the pharmacokinetic parameters of Pt did not significantly differ between the treatments. Also, the unbound fraction determined at each sampling time did not vary significantly between the treatments. However, it is noteworthy that the mean values obtained for the terminal half-life, the volume of distribution, the renal clearance, the percentage of the dose excreted in the urine, and the mean residence time of total Pt were higher in patients who had been pretreated with GSH, suggesting that GSH might increase both the rate of Pt elimination and the extent of Pt distribution and, as a consequence of the latter, might prolong the residence time of Pt in the body. In addition, the unbound fraction of Pt from the 4th to the 48th was higher following the first dose of CDDP+GSH than after treatment with CDDP alone. Because of the rather high variability in the values of the parameters obtained, further work is planned using a larger number of patients.
Leone
R
R
Institute of Pharmacology, Policlinico Borgo Roma, Verona, Italy.
Fracasso
M E
ME
Soresi
E
E
Cimino
G
G
Tedeschi
M
M
Castoldi
D
D
Monzani
V
V
Colombi
L
L
Usari
T
T
Bernareggi
A
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000008:administration & dosage; D005978:Glutathione / Q000008:administration & dosage*; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism; D010984:Platinum / Q000032:analysis / Q000493:pharmacokinetics*; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
D010984:Platinum; D005047:Etoposide; D005978:Glutathione; D002945:Cisplatin