TY - JOUR
T1 - Time-dependent nephrotoxicity associated with daily administration of cisplatin in Mice
AU - To, H.
AU - Kikuchi, A.
AU - Tsuruoka, S.
AU - Sugimoto, K.
AU - Fujimura, A.
AU - Higuchi, S.
AU - Kayama, F.
AU - Hara, K.
AU - Matsuno, K.
AU - Kobayashi, E.
PY - 2000
Y1 - 2000
N2 - The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6 mg kg-1) for 5 days at four time points (04 00, 10 00, 16 00 and 22 00 h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04 00 and 16 00 h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04 00 and 16 00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04 00 and the 16 00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16 00 h group than in the 04 00 h group after saline injection alone (P <0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.
AB - The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6 mg kg-1) for 5 days at four time points (04 00, 10 00, 16 00 and 22 00 h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04 00 and 16 00 h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04 00 and 16 00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04 00 and the 16 00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16 00 h group than in the 04 00 h group after saline injection alone (P <0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.
UR - http://www.scopus.com/inward/record.url?scp=17744399916&partnerID=8YFLogxK
U2 - 10.1211/0022357001777711
DO - 10.1211/0022357001777711
M3 - 学術論文
C2 - 11197078
AN - SCOPUS:17744399916
SN - 0022-3573
VL - 52
SP - 1499
EP - 1504
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
IS - 12
ER -