[Pharmacokinetics and changes of reduced folate levels in tumor after administration of cisplatin].
Cisplatin acts as a biochemical modulator of 5-FU to increase the intracellular concentration of reduced folates. To determine the optimum schedule for administering cisplatin as a 5-FU modulator, we analyzed pharmacokinetics of platinum and changes of reduced folate levels in the tumor following administration of cisplatin in Yoshida sarcoma-bearing rats. Clinical kinetics of cisplatin was also investigated. The reduced folate level in the tumor was temporarily increased 2-1.6 fold of the control level 1-2 hours after the rapid injection of cisplatin (4 mg/kg). The folate level 2 hours after the rapid injection of cisplatin increased dose-dependently within the dose of 1mg/kg and reached to the plateau with the doses of 1, 2, 4, 8 mg/kg, although the platinum concentration in plasma and tumor increased linearly correlated with the dose of cisplatin. These findings suggest the modulatory effect through rapid injection of cisplatin is transiently exerted only in the early phase, and not dose-dependently but limitatively with the dose of 1 mg/kg or more. Therefore, repeated administration with low dose or continuous infusion of cisplatin simultaneous with 5-FU derivatives is desirable for combination chemotherapy. Clinically, the minimum effective dose of cisplatin as a modulator was thought to be 10-20 mg/body judging from experimental as well as clinical kinetic study of cisplatin.
Hashimoto
T
T
Dept. of Surgery (1), School of Medicine, Kanazawa University.
Omura
K
K
Sunohara
T
T
Osari
A
A
Yasuda
T
T
Kawakami
K
K
Matsu
T
T
Ishida
F
F
Watanabe
Y
Y
Fukushima
M
M
D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage; D005557:Formaldehyde / Q000032:analysis*; D008297:Male; D010984:Platinum / Q000097:blood; D051381:Rats; D012517:Sarcoma, Yoshida / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000032:analysis*
D013763:Tetrahydrofolates; D005557:Formaldehyde; C030371:5,6,7,8-tetrahydrofolic acid; D010984:Platinum; D002945:Cisplatin; D005472:Fluorouracil