Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1994 Mar;38(3):504–510. doi: 10.1128/aac.38.3.504

Pharmacokinetics of antiviral polyoxometalates in rats.

L Ni 1, F D Boudinot 1, S G Boudinot 1, G W Henson 1, G E Bossard 1, S A Martellucci 1, P W Ash 1, S P Fricker 1, M C Darkes 1, B R Theobald 1, et al.
PMCID: PMC284488  PMID: 8203845

Abstract

Polyoxometalates are soluble mineral compounds formed principally of oxide anions and early transition metal cations. The polyoxometalates K12H2[P2W12O48].24H2O (JM 1591), K10[P2W18Zn4(H2O)2O68].20H2O (JM 1596), and [(CH3)3NH]8[Si2W18Nb6O77] (JM 2820) demonstrate potent antiviral activity against human immunodeficiency virus types 1 and 2, herpes simplex virus, and cytomegalovirus in vitro. The preclinical pharmacokinetics of these three compounds were characterized after single-dose intravenous administration of 50 mg/kg to rats. Plasma, urine, and feces were collected for 168 h, and polyoxometalate concentrations were determined by atomic emission. Serum protein binding was measured by equilibrium dialysis. All three compounds were highly bound to serum proteins in a concentration-dependent manner. Total and unbound concentrations of the three compounds in plasma declined in a triexponential manner with terminal half-lives of 246.0 +/- 127.0, 438.4 +/- 129.4, and 32.2 +/- 5.37 h (mean +/- standard deviation) for JM 1591, JM 1596, and JM 2820, respectively. Systemic clearances based on total concentrations in plasma were low, averaging 0.016 +/- 0.002, 0.015 +/- 0.002, and 0.018 +/- 0.003 liter/h/kg for JM 1591, JM 1596, and JM 2820, respectively. The clearances of unbound compounds from plasma averaged 0.966 +/- 0.136, 0.050 +/- 0.005, and 0.901 +/- 0.165 liter/h/kg for JM 1591, JM 1596, and JM 2820, respectively. For JM 1596, the clearance of unbound compound from the kidneys was lower than the glomerular filtration rate (0.086 liter/h/kg), suggesting this polyoxometalate underwent renal tubular reabsorption. However, JM 1591 and JM 2820 appeared to undergo tubular secretion. The fraction of the dose recovered in urine was 11.5, 46.8, and 10.6% for JM 1591, JM 1596, and JM 2820, respectively. Approximately 5% of the dose of each polyoxometalate was recovered in feces. The steady-state volume of distribution based on total concentrations averaged 1.44 liters/kg for JM 1591, 2.39 liters/kg for JM 1596, and 0.59 liter/kg for JM 2820, indicating moderate to wide distribution throughout the body. All three compounds were detected in various tissues 1 week after single-dose administrations, with the highest levels found in the kidneys and liver. The results of this study indicate that the disposition of polyoxometalates is highly dependent on their molecular structure.

Full text

PDF
504

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berry J. P., Galle P. Subcellular localization of HPA-23 in different rat organs: electron microprobe study. Exp Mol Pathol. 1990 Dec;53(3):255–264. doi: 10.1016/0014-4800(90)90048-i. [DOI] [PubMed] [Google Scholar]
  2. Boudinot F. D., Jusko W. J. Fluid shifts and other factors affecting plasma protein binding of prednisolone by equilibrium dialysis. J Pharm Sci. 1984 Jun;73(6):774–780. doi: 10.1002/jps.2600730617. [DOI] [PubMed] [Google Scholar]
  3. Burgard M., Sansonetti P., Vittecoq D., Descamps P., Guetard D., Herson S., Rozenbaum W., Rouzioux C. Lack of HPA-23 antiviral activity in HIV-infected patients without AIDS. AIDS. 1989 Oct;3(10):665–668. doi: 10.1097/00002030-198910000-00009. [DOI] [PubMed] [Google Scholar]
  4. Dormont D., Yeramian P., Lambert P., Spire B., Daveloose D., Barre-Sinoussi F. C., Chermann J. C. Cellular and molecular mechanisms of antiretroviral effects of HPA23. Cancer Detect Prev. 1988;12(1-6):181–194. [PubMed] [Google Scholar]
  5. Fischer J., Ricard L., Weiss R. The structure of the heteropolytungstate (NH4)17Na NaW21Sb9O86-14H2O. An inorganic crypate. J Am Chem Soc. 1976 May 12;98(10):3050–3052. doi: 10.1021/ja00426a081. [DOI] [PubMed] [Google Scholar]
  6. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  7. Gerlowski L. E., Jain R. K. Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci. 1983 Oct;72(10):1103–1127. doi: 10.1002/jps.2600721003. [DOI] [PubMed] [Google Scholar]
  8. Gilboa E., Mitra S. W., Goff S., Baltimore D. A detailed model of reverse transcription and tests of crucial aspects. Cell. 1979 Sep;18(1):93–100. doi: 10.1016/0092-8674(79)90357-x. [DOI] [PubMed] [Google Scholar]
  9. Gottlieb M. S., Schroff R., Schanker H. M., Weisman J. D., Fan P. T., Wolf R. A., Saxon A. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med. 1981 Dec 10;305(24):1425–1431. doi: 10.1056/NEJM198112103052401. [DOI] [PubMed] [Google Scholar]
  10. Hill C. L., Weeks M. S., Schinazi R. F. Anti-HIV-1 activity, toxicity, and stability studies of representative structural families of polyoxometalates. J Med Chem. 1990 Oct;33(10):2767–2772. doi: 10.1021/jm00172a014. [DOI] [PubMed] [Google Scholar]
  11. Hoffman M. New vector delivers genes to lung cells. Science. 1991 Apr 19;252(5004):374–374. doi: 10.1126/science.2017677. [DOI] [PubMed] [Google Scholar]
  12. Inouye Y., Tokutake Y., Yoshida T., Yamamoto A., Yamase T., Nakamura S. Antiviral activity of polyoxomolybdoeuropate PM-104 against human immunodeficiency virus type 1. Chem Pharm Bull (Tokyo) 1991 Jun;39(6):1638–1640. doi: 10.1248/cpb.39.1638. [DOI] [PubMed] [Google Scholar]
  13. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  14. Larder B. A., Kemp S. D. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science. 1989 Dec 1;246(4934):1155–1158. doi: 10.1126/science.2479983. [DOI] [PubMed] [Google Scholar]
  15. Mitsuya H., Broder S. Antiretroviral chemotherapy against human immunodeficiency virus (hiv) infection: perspective for therapy of hepatitis B virus infection. Cancer Detect Prev. 1989;14(2):299–308. [PubMed] [Google Scholar]
  16. Mitsuya H., Broder S. Strategies for antiviral therapy in AIDS. 1987 Feb 26-Mar 4Nature. 325(6107):773–778. doi: 10.1038/325773a0. [DOI] [PubMed] [Google Scholar]
  17. Mitsuya H., Yarchoan R., Broder S. Molecular targets for AIDS therapy. Science. 1990 Sep 28;249(4976):1533–1544. doi: 10.1126/science.1699273. [DOI] [PubMed] [Google Scholar]
  18. Moskovitz B. L. Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome. Antimicrob Agents Chemother. 1988 Sep;32(9):1300–1303. doi: 10.1128/aac.32.9.1300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Patel B. A., Chu C. K., Boudinot F. D. Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats. J Pharm Sci. 1989 Jul;78(7):530–534. doi: 10.1002/jps.2600780704. [DOI] [PubMed] [Google Scholar]
  20. Richman D. D., Fischl M. A., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Hirsch M. S. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
  21. Richman D. D. Zidovudine resistance of human immunodeficiency virus. Rev Infect Dis. 1990 Jul-Aug;12 (Suppl 5):S507–S512. doi: 10.1093/clinids/12.supplement_5.s507. [DOI] [PubMed] [Google Scholar]
  22. Rocci M. L., Jr, Jusko W. J. LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed. 1983 Jun;16(3):203–216. doi: 10.1016/0010-468x(83)90082-x. [DOI] [PubMed] [Google Scholar]
  23. Rooke R., Tremblay M., Soudeyns H., DeStephano L., Yao X. J., Fanning M., Montaner J. S., O'Shaughnessy M., Gelmon K., Tsoukas C. Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS. 1989 Jul;3(7):411–415. doi: 10.1097/00002030-198907000-00001. [DOI] [PubMed] [Google Scholar]
  24. Rose J. Q., Yurchak A. M., Jusko W. J. Dose dependent pharmacokinetics of prednisone and prednisolone in man. J Pharmacokinet Biopharm. 1981 Aug;9(4):389–417. doi: 10.1007/BF01060885. [DOI] [PubMed] [Google Scholar]
  25. Schinazi R. F., Mead J. R., Feorino P. M. Insights into HIV chemotherapy. AIDS Res Hum Retroviruses. 1992 Jun;8(6):963–990. doi: 10.1089/aid.1992.8.963. [DOI] [PubMed] [Google Scholar]
  26. Take Y., Tokutake Y., Inouye Y., Yoshida T., Yamamoto A., Yamase T., Nakamura S. Inhibition of proliferation of human immunodeficiency virus type 1 by novel heteropolyoxotungstates in vitro. Antiviral Res. 1991 Feb;15(2):113–124. doi: 10.1016/0166-3542(91)90029-q. [DOI] [PubMed] [Google Scholar]
  27. Van Roey P., Taylor E. W., Chu C. K., Schinazi R. F. Correlation of molecular conformation and activity of reverse transcriptase inhibitors. Ann N Y Acad Sci. 1990;616:29–40. doi: 10.1111/j.1749-6632.1990.tb17825.x. [DOI] [PubMed] [Google Scholar]
  28. Weeks M. S., Hill C. L., Schinazi R. F. Synthesis, characterization, and anti-human immunodeficiency virus activity of water-soluble salts of polyoxotungstate anions with covalently attached organic groups. J Med Chem. 1992 Apr 3;35(7):1216–1221. doi: 10.1021/jm00085a008. [DOI] [PubMed] [Google Scholar]
  29. Wilkinson G. R. Plasma and tissue binding considerations in drug disposition. Drug Metab Rev. 1983;14(3):427–465. doi: 10.3109/03602538308991396. [DOI] [PubMed] [Google Scholar]
  30. Yamamoto N., Schols D., De Clercq E., Debyser Z., Pauwels R., Balzarini J., Nakashima H., Baba M., Hosoya M., Snoeck R. Mechanism of anti-human immunodeficiency virus action of polyoxometalates, a class of broad-spectrum antiviral agents. Mol Pharmacol. 1992 Dec;42(6):1109–1117. [PubMed] [Google Scholar]
  31. Yamaoka K., Nakagawa T., Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978 Apr;6(2):165–175. doi: 10.1007/BF01117450. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES