Skip to main content
SpringerLink
Log in

Effects of Disopyramide and Verapamil on Renal Disposition and Nephrotoxicity of Cisplatin in Rats

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. P. J. Stone, A. D. Kelman, and F. M. Sinex. Specific binding of antitumour drug cisPt(NH3)2Cl2 to DNA rich in guanine and cytosine. Nature 251:736–737 (1974).

    Google Scholar 

  2. F. F. Farris, F. G. King, R. L. Dedrick, and C. L. Litterst. Physiological model for the pharmacokinetics of cis-dichlorodiammineplatinum(II) (DDP) in the tumored rat. J. Pharmacokin. Biopharm. 13:13–40 (1985).

    Google Scholar 

  3. N. Nagai, R. Okuda, M. Kinoshita, and H. Ogata. Decomposition kinetics of cisplatin in human biological fluids. J. Pharm. Pharmacol. 48:918–924 (1996).

    Google Scholar 

  4. K. Hanada, N. Nagai, and H. Ogata. Toxicokinetics of cisplatin in rats (Abstract). XIIth International Congress of Pharmacology, 24–29 July (1994), Montreal, Canada; Can. J. Physiol. Pharmacol. 587 (1994).

  5. N. Nagai, K. Hotta, M. Yamamura, and H. Ogata. Effect of sodium thiosulfate on the pharmacokinetics of unchanged cisplatin and on the accumulation of platinum species in rat kidney: protective mechanism against cisplatin nephrotoxicity. Cancer Chemother. Pharmacol 36:404–412 (1995).

    Google Scholar 

  6. C. Jacobs, S. Kaubisch, J. Halsey, B. L. Lum, M. Gosland, N. Coleman, and B. I. Sikic. The use of probenecid as a chemoprotector against cisplatin nephrotoxicity. Cancer 67:1518–1524 (1991).

    Google Scholar 

  7. J. Klein, Y. Bentur, D. Cheung, G. Moselhy, and G. Koren. Renal handling of cisplatin: interactions with organic anions and cations in the dog. Clin. Invest. Med. 14:388–394 (1991).

    Google Scholar 

  8. R. Safirstein, P. Miller, and J. B. Guttenplan. Uptake and metabolism of cisplatin by rat kidney. Kidney Int. 25:753–758 (1984).

    Google Scholar 

  9. Y. Harada, E. Kumagai, N. Nagai, K. Hanada, and H. Ogata. Uptake of cisplatin and its metabolites in rat and rabbit renal cortical slices. Pharm. Pharmacol. Commun. 4:455–458 (1998).

    Google Scholar 

  10. Y. Takahashi, T. Itoh, M. Kobayashi, M. Sugawara, H. Saitoh, K. Iseki, K. Miyazaki, S. Miyazaki, M. Takada, Y. Kawashima. The transport mechanism of an organic cation, disopyramide, by brash-border membranes. J. Pharm. Pharmacol. 45:419–424 (1993).

    Google Scholar 

  11. K. Hanada, S. Akimoto, K. Mitsui, M. Hashiguchi, and H. Ogata. Quantitative determination of disopyramide, flecainide and verapamil in rat plasma and tissues by high performance liquid chromatography. J. Chromatogr. B 710:129–135 (1998).

    Google Scholar 

  12. N. Nagai and H. Ogata. Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determination in vivo. Cancer Chemother. Pharmacol. 40:11–18 (1997).

    Google Scholar 

  13. K. Hanada, N. Nagai, and H. Ogata. Quantitative determination of unchanged cisplatin in rat kidney and liver by high-performance liquid chromatography. J. Chromatogr. B 663:181–186 (1995).

    Google Scholar 

  14. R. P. White and F. E. Jr. Samson. Determination of inulin in plasma and urine by use of anthrone. J. Lab. Clin. Med. 43:475–478 (1954).

    Google Scholar 

  15. M. Gibaldi and D. Perrier. Noncompartmental analysis based on statistical moment theory. In Pharmacokinetics 2nd edn (M. Gibaldi and D. Perrier Ed.), pp. 409, Marcel Dekker Inc., New York (1982).

    Google Scholar 

  16. Y. Sugiyama, M. Hanano, and Y. Sawada. Program NLS (in Japanese). In Pharmacokinetics (M. Hanano, Ed.), pp. 113–127, Nanzando Press, Tokyo (1987).

    Google Scholar 

  17. H. B. Lin and D. B. Young. Verapamil alters the relationship between renal perfusion pressure and glomerular filtration rate and renin release: the mechanism of the antihypertensive effect. J. Cardiovasc. Pharmacol 12:S57–S59 (1988).

    Google Scholar 

  18. P. D. Williams and G. H. Hottendorf. Effect of cisplatin on organic ion transport in membrane vesicles from rat kidney cortex. Cancer Treat. Rep. 69:875–880 (1985).

    Google Scholar 

  19. J. J. G. Offerman, S. Meijer, D. T. Sleijfer, N.H. Mulder, A. J. M. Donker, H. S. Koops, and G. K. Hem. The influence of verapamil on renal function in patients treated with cisplatin. Clin. Nephrol. 24:249–255 (1985).

    Google Scholar 

  20. D. T. Sleijfer, J. J. G. Offerman, N. H. Mulder, M. Verweij, G. K. Hem, H. S. Koops, and S. Meijer. The protective potential of the combination of verapamil and cimetidine on cisplatin-induced nephrotoxicity in man. Cancer 60:2823–2828 (1987).

    Google Scholar 

  21. M. Hashiguchi, H. Ogata, A. Maeda, Y. Harashima, S. Ishii, Y. Mori, T. Amamoto, T. Handa, N. Otsuka, S. Irie, A. Urae, R. Urae, and R. Kimura. No effects of high-protein food on the stereoselective bioavailability and pharmacokinetics of verapamil. J. Clin. Pharmacol. 36:1022–1028 (1996).

    Google Scholar 

  22. L. Williams and H. Lee. Importance of drug enantiomers in clinical pharmacology. Drugs 32:333–354 (1985).

    Google Scholar 

  23. R. J. Ott and K. M. Giacomini. Stereoselective interactions of organic cations with the organic cation transporter in OK cells. Pharm. Res. 10:1169–1173 (1993).

    Google Scholar 

  24. R. Safirstein, J. Winston, D. Moel, S. Dikman, and J. Guttenplan. Cisplatin nephrotoxicity: insights into mechanism. Int. J. Androl. 10:325–346 (1987).

    Google Scholar 

  25. P. T. Daley-Yates and D. C. H. McBrien. The mechanism of renal clearance of cisplatin (cis-dichlorodiammine platinum II) and its modification by furosemide and probenecid. Biochem. Pharmacol. 31:2243–2246 (1982).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biopharmaceutics, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose-shi, Tokyo, 204-8588, Japan

    Kazuhiko Hanada, Kentaro Odaka, Akemi Kudo & Hiroyasu Ogata

Authors
  1. Kazuhiko Hanada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kentaro Odaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akemi Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyasu Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroyasu Ogata.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanada, K., Odaka, K., Kudo, A. et al. Effects of Disopyramide and Verapamil on Renal Disposition and Nephrotoxicity of Cisplatin in Rats. Pharm Res 16, 1589–1595 (1999). https://doi.org/10.1023/A:1018912806355

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018912806355

Search

Navigation