Mechanism of the protective effect of sodium malate on cisplatin-induced toxicity in mice.
We examined the mechanism of the protective effect of sodium malate on cis-diamminedichloroplatinum(II) (cisplatin, CDDP)-induced nephrotoxicity in mice and obtained the following findings: 1: Sodium malate showed a maximum reduction of toxicity when it was administered at the same time as CDDP or at 30 min before the administration of CDDP; the reduction was significantly decreased when sodium malate was given after the administration of CDDP. 2: It is thought that diamminoplatinum(II) malate (DPM) is produced in the body following the administration of a combination of CDDP and sodium malate. DPM showed the same antitumor effect as CDDP and produced little nephrotoxicity. 3: When CDDP was combined with sodium malate, the time necessary for the elimination of platinum from the blood was prolonged, showing a intermediate value between the times for the elimination of CDDP and DPM from the blood. When the drug clearance was calculated based on this result, it was found that about 40% of the CDDP administered is converted to DPM in the blood. 4: In an experiment using L-[14C] malic acid, it was shown that sodium malate is distributed in the liver and the kidney at high concentrations, but in the tumor at only a low concentration. 5: When sodium malate was administered in combination with CDDP, the amount of platinum which accumulated in the kidney after 24 h was decreased by about 55% compared with the uncombined group, but there was no change in the amount of platinum which accumulated in the tumor. These results suggest that the sodium malate administered may be distributed rapidly in the blood and the tissue, and about 40% is bound to CDDP and converted to DPM, thus reducing the nephrotoxicity of CDDP.
Ueda
H
H
Institute of Traditional Chinese Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Yada, Japan.
Sugiyama
K
K
Tashiro
S
S
Yokota
M
M
D000818:Animals; D000931:Antidotes / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002945:Cisplatin / Q000633:toxicity*; D006207:Half-Life; D008293:Malates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009944:Organoplatinum Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
D000931:Antidotes; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D008293:Malates; D009944:Organoplatinum Compounds; C111426:diaminoplatinum(II)malate; C030298:malic acid; D002945:Cisplatin