Effects of disopyramide and verapamil on renal disposition and nephrotoxicity of cisplatin in rats.
OBJECTIVE
The purpose of this study was to determine the effects of disopyramide and verapamil on the renal handling of cisplatin (CDDP) and nephrotoxicity in rats. The stereoselective effect of verapamil was also studied.


METHODS
CDDP was administered to rats by i.v. bolus injection or by infusion at a constant rate with or without concomitant administration of racemic disopyramide, racemic verapamil, or each verapamil enantiomer. The concentrations of CDDP in plasma and in the kidney and liver were determined by HPLC. In separate experiments, CDDP was administered as described above, and blood urea nitrogen (BUN) was monitored for 7 days.


RESULTS
The BUN level after administration of CDDP was significantly reduced by coadministration of either disopyramide or verapamil. Renal accumulation of CDDP was significantly reduced by these drugs, whereas accumulation into the liver was not significantly changed. The relationship between the BUN levels and the area under the curve of CDDP concentration in the kidney versus time (AUCk) was analyzed using a sigmoid Emax model; this showed that the reduced BUN levels were explained by the AUCk. Furthermore, verapamil showed stereoselective inhibition of the renal accumulation of CDDP.


CONCLUSIONS
The renal accumulation of CDDP was inhibited by disopyramide and verapamil, and this inhibition resulted in the amelioration of nephrotoxicity.
Hanada
K
K
Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose-shi, Tokyo, Japan.
Odaka
K
K
Kudo
A
A
Ogata
H
H
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D019540:Area Under Curve; D001711:Biotransformation; D001806:Blood Urea Nitrogen; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D004206:Disopyramide / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D010984:Platinum / Q000097:blood / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D010984:Platinum; D014700:Verapamil; D004206:Disopyramide; D002945:Cisplatin