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. 1996 Aug;40(8):1806–1810. doi: 10.1128/aac.40.8.1806

Evaluation of renal toxicity and antifungal activity of free and liposomal amphotericin B following a single intravenous dose to diabetic rats with systemic candidiasis.

K M Wasan 1, J S Conklin 1
PMCID: PMC163421  PMID: 8843285

Abstract

Since fungal infections are prevalent in diabetic patients, in whom treatment is often complicated by underlying renal disease and dyslipidemias, the purpose of the present study was to determine if the antifungal activity and nephrotoxic effects of amphotericin B (AmB) and liposomal AmB (L-AmB) are different in nondiabetic (normolipidemic) rats compared with those in diabetic (dyslipidemic) rats with systemic candidiasis. Non diabetic and diabetic rats infected with Candida albicans received a single intravenous dose of either AmB (0.8 mg of AmB per kg of body weight), L-AmB (0.8, 2, or 4 mg of AmB per kg), or an equivalent volume of normal saline (1 ml). Renal function was assessed by insulin clearance, and antifungal activity was determined by measuring the numbers of CFU of C. albicans that were present in the right kidney following drug treatment. AmB at 0.8 mg/kg and L-AmB at 0.8, 2, and 4 mg/kg are effective antifungal agents in both diabetic and nondiabetic rats. However, while there was approximately a 4-fold decline in the mean number of CFU per gram of kidney in nondiabetic rats, there was only approximately a 2.5-fold decline for the comparable dose (AmB, 0.8 mg/kg) in diabetic rats. There also appeared to be a similar fold reduction of L-AmB at all of the dosages tested. AmB treatment significantly improved renal function in diabetic and nondiabetic rats with systemic candidiasis. Although L-AmB at all doses tested significantly improved renal function in diabetic rats with systemic candidiasis, only L-AmB at doses of 2 and 4 mg/kg significantly improved renal function in nondiabetic rats with systemic candidiasis. These findings suggest that following administration of a single intravenous dose, AmB and L-AmB appear to be less effective in killing C. albicans isolates in diabetic than in nondiabetic rats, while they were found to improve the renal functions of rats in both treatment groups.

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Selected References

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  1. Chabot G. G., Pazdur R., Valeriote F. A., Baker L. H. Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients. J Pharm Sci. 1989 Apr;78(4):307–310. doi: 10.1002/jps.2600780409. [DOI] [PubMed] [Google Scholar]
  2. Feingold K. R., Krauss R. M., Pang M., Doerrler W., Jensen P., Grunfeld C. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab. 1993 Jun;76(6):1423–1427. doi: 10.1210/jcem.76.6.8501146. [DOI] [PubMed] [Google Scholar]
  3. Grunfeld C., Pang M., Doerrler W., Shigenaga J. K., Jensen P., Feingold K. R. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992 May;74(5):1045–1052. doi: 10.1210/jcem.74.5.1373735. [DOI] [PubMed] [Google Scholar]
  4. Janoff A. S., Boni L. T., Popescu M. C., Minchey S. R., Cullis P. R., Madden T. D., Taraschi T., Gruner S. M., Shyamsunder E., Tate M. W. Unusual lipid structures selectively reduce the toxicity of amphotericin B. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6122–6126. doi: 10.1073/pnas.85.16.6122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Laakso M., Pyörälä K. Lipid and lipoprotein abnormalities in diabetic patients with peripheral vascular disease. Atherosclerosis. 1988 Nov;74(1-2):55–63. doi: 10.1016/0021-9150(88)90191-8. [DOI] [PubMed] [Google Scholar]
  6. Lopez-Berestein G., Bodey G. P., Fainstein V., Keating M., Frankel L. S., Zeluff B., Gentry L., Mehta K. Treatment of systemic fungal infections with liposomal amphotericin B. Arch Intern Med. 1989 Nov;149(11):2533–2536. [PubMed] [Google Scholar]
  7. Lopez-Berestein G., Fainstein V., Hopfer R., Mehta K., Sullivan M. P., Keating M., Rosenblum M. G., Mehta R., Luna M., Hersh E. M. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study. J Infect Dis. 1985 Apr;151(4):704–710. doi: 10.1093/infdis/151.4.704. [DOI] [PubMed] [Google Scholar]
  8. Lopez-Berestein G., Hopfer R. L., Mehta R., Mehta K., Hersh E. M., Juliano R. L. Liposome-encapsulated amphotericin B for treatment of disseminated candidiasis in neutropenic mice. J Infect Dis. 1984 Aug;150(2):278–283. doi: 10.1093/infdis/150.2.278. [DOI] [PubMed] [Google Scholar]
  9. Lopez-Berestein G., Hopfer R. L., Mehta R., Mehta K., Hersh E. M., Juliano R. L. Prophylaxis of Candida albicans infection in neutropenic mice with liposome-encapsulated amphotericin B. Antimicrob Agents Chemother. 1984 Mar;25(3):366–367. doi: 10.1128/aac.25.3.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lopez-Berestein G. Liposomes as carriers of antifungal drugs. Ann N Y Acad Sci. 1988;544:590–597. doi: 10.1111/j.1749-6632.1988.tb40459.x. [DOI] [PubMed] [Google Scholar]
  11. Lopez-Berestein G., Mehta R., Hopfer R. L., Mills K., Kasi L., Mehta K., Fainstein V., Luna M., Hersh E. M., Juliano R. Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin B. J Infect Dis. 1983 May;147(5):939–945. doi: 10.1093/infdis/147.5.939. [DOI] [PubMed] [Google Scholar]
  12. Lopez-Berestein G., Rosenblum M. G., Mehta R. Altered tissue distribution of amphotericin B by liposomal encapsulation: comparison of normal mice to mice infected with Candida albicans. Cancer Drug Deliv. 1984 Summer;1(3):199–205. doi: 10.1089/cdd.1984.1.199. [DOI] [PubMed] [Google Scholar]
  13. Luke D. R., Wasan K. M., Verani R. R., Brunner L. J., Berens K. L., Vadiei K., Lopez-Berestein G. Attenuation of amphotericin-B nephrotoxicity in the candidiasis rat model. Nephron. 1991;59(1):139–144. doi: 10.1159/000186533. [DOI] [PubMed] [Google Scholar]
  14. Medoff G., Brajtburg J., Kobayashi G. S., Bolard J. Antifungal agents useful in therapy of systemic fungal infections. Annu Rev Pharmacol Toxicol. 1983;23:303–330. doi: 10.1146/annurev.pa.23.040183.001511. [DOI] [PubMed] [Google Scholar]
  15. Mehta R. T., McQueen T. J., Keyhani A., López-Berestein G. Phagocyte transport as mechanism for enhanced therapeutic activity of liposomal amphotericin B. Chemotherapy. 1994 Jul-Aug;40(4):256–264. doi: 10.1159/000239202. [DOI] [PubMed] [Google Scholar]
  16. Morton R. E. Interaction of lipid transfer protein with plasma lipoproteins and cell membranes. Experientia. 1990 Jun 15;46(6):552–560. doi: 10.1007/BF01939693. [DOI] [PubMed] [Google Scholar]
  17. Morton R. E., Zilversmit D. B. Inter-relationship of lipids transferred by the lipid-transfer protein isolated from human lipoprotein-deficient plasma. J Biol Chem. 1983 Oct 10;258(19):11751–11757. [PubMed] [Google Scholar]
  18. Nicholl T., Phillips P., Jewesson P. J. Amphotericin B use in a major acute care hospital. Clin Ther. 1994 Jan-Feb;16(1):28–27. [PubMed] [Google Scholar]
  19. Tolins J. P., Raij L. Adverse effect of amphotericin B administration on renal hemodynamics in the rat. Neurohumoral mechanisms and influence of calcium channel blockade. J Pharmacol Exp Ther. 1988 May;245(2):594–599. [PubMed] [Google Scholar]
  20. Venkataram S., Awni W. M., Jordan K., Rahman Y. E. Pharmacokinetics of two alternative dosage forms for cyclosporine: liposomes and intralipid. J Pharm Sci. 1990 Mar;79(3):216–219. doi: 10.1002/jps.2600790307. [DOI] [PubMed] [Google Scholar]
  21. Wasan K. M., Brazeau G. A., Keyhani A., Hayman A. C., Lopez-Berestein G. Roles of liposome composition and temperature in distribution of amphotericin B in serum lipoproteins. Antimicrob Agents Chemother. 1993 Feb;37(2):246–250. doi: 10.1128/aac.37.2.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wasan K. M., Grossie V. B., Jr, Lopez-Berestein G. Concentrations in serum and distribution in tissue of free and liposomal amphotericin B in rats during continuous intralipid infusion. Antimicrob Agents Chemother. 1994 Sep;38(9):2224–2226. doi: 10.1128/aac.38.9.2224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wasan K. M., Lopez-Berestein G. The influence of serum lipoproteins on the pharmacokinetics and pharmacodynamics of lipophilic drugs and drug carriers. Arch Med Res. 1993 Winter;24(4):395–401. [PubMed] [Google Scholar]
  24. Wasan K. M., Morton R. E., Rosenblum M. G., Lopez-Berestein G. Decreased toxicity of liposomal amphotericin B due to association of amphotericin B with high-density lipoproteins: role of lipid transfer protein. J Pharm Sci. 1994 Jul;83(7):1006–1010. doi: 10.1002/jps.2600830716. [DOI] [PubMed] [Google Scholar]
  25. Wasan K. M., Rosenblum M. G., Cheung L., Lopez-Berestein G. Influence of lipoproteins on renal cytotoxicity and antifungal activity of amphotericin B. Antimicrob Agents Chemother. 1994 Feb;38(2):223–227. doi: 10.1128/aac.38.2.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wasan K. M., Vadiei K., Lopez-Berestein G., Luke D. R. Pharmacokinetics, tissue distribution, and toxicity of free and liposomal amphotericin B in diabetic rats. J Infect Dis. 1990 Mar;161(3):562–566. doi: 10.1093/infdis/161.3.562. [DOI] [PubMed] [Google Scholar]

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