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. 1997 Oct;41(10):2184–2187. doi: 10.1128/aac.41.10.2184

Pharmacokinetics of 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil in woodchucks.

J W Witcher 1, F D Boudinot 1, B H Baldwin 1, M A Ascenzi 1, B C Tennant 1, J F Du 1, C K Chu 1
PMCID: PMC164090  PMID: 9333045

Abstract

1-(2-Fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU) is a nucleoside analog with potent in vitro activity against hepatitis B virus (HBV) and Epstein-Barr virus. The purpose of this study was to characterize the disposition of L-FMAU following oral and intravenous administration in the woodchuck animal model. The numerous similarities between woodchuck hepatitis virus and HBV infection justify the use of the woodchuck as an animal model for preclinical studies of anti-HBV agents in vivo. Woodchucks were given 25 mg of L-FMAU per kg of body weight intravenously and orally. Concentrations of L-FMAU in urine and plasma were determined by high-performance liquid chromatography. Following intravenous administration of 25 mg of L-FMAU per kg to woodchucks, total clearance was moderate, averaging 0.23 +/- 0.07 liter/h/kg. Renal clearance and nonrenal clearance averaged 0.13 +/- 0.08 and 0.10 +/- 0.06 liter/h/kg, respectively. The steady-state volume of distribution averaged 0.99 +/- 0.17 liter/kg, indicative of intracellular distribution of the nucleoside. The terminal-phase half-life of L-FMAU following intravenous administration averaged 6.2 +/- 2.0 h, and mean residence time averaged 4.5 +/- 0.8 h. Absorption of L-FMAU after oral administration was incomplete, and bioavailability was approximately 20%. Concentrations of L-FMAU in plasma remained above the in vitro 50% effective concentration of 0.026 microg/ml for HBV (C. K. Chu, T. Ma, K. Shanmuganathan, C. Wang, Y. Xiang, S. B. Pai, G.-Q. Yao, J.-P. Sommadossi, and Y.-C. Cheng, Antimicrob. Agents Chemother. 39:979-981, 1995) for 24 h after both intravenous and oral administration of 25 mg of L-FMAU per kg.

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Selected References

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  1. Blumberg B. S., Gerstley B. J., Hungerford D. A., London W. T., Sutnick A. I. A serum antigen (Australia antigen) in Down's syndrome, leukemia, and hepatitis. Ann Intern Med. 1967 May;66(5):924–931. doi: 10.7326/0003-4819-66-5-924. [DOI] [PubMed] [Google Scholar]
  2. Chu C. K., Ma T., Shanmuganathan K., Wang C., Xiang Y., Pai S. B., Yao G. Q., Sommadossi J. P., Cheng Y. C. Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus. Antimicrob Agents Chemother. 1995 Apr;39(4):979–981. doi: 10.1128/aac.39.4.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dienstag J. L., Perrillo R. P., Schiff E. R., Bartholomew M., Vicary C., Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med. 1995 Dec 21;333(25):1657–1661. doi: 10.1056/NEJM199512213332501. [DOI] [PubMed] [Google Scholar]
  4. Hoofnagle J. H., Peters M., Mullen K. D., Jones D. B., Rustgi V., Di Bisceglie A., Hallahan C., Park Y., Meschievitz C., Jones E. A. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology. 1988 Nov;95(5):1318–1325. doi: 10.1016/0016-5085(88)90367-8. [DOI] [PubMed] [Google Scholar]
  5. Korba B. E., Gowans E. J., Wells F. V., Tennant B. C., Clarke R., Gerin J. L. Systemic distribution of woodchuck hepatitis virus in the tissues of experimentally infected woodchucks. Virology. 1988 Jul;165(1):172–181. doi: 10.1016/0042-6822(88)90670-8. [DOI] [PubMed] [Google Scholar]
  6. Korba B. E., Wells F., Tennant B. C., Cote P. J., Gerin J. L. Lymphoid cells in the spleens of woodchuck hepatitis virus-infected woodchucks are a site of active viral replication. J Virol. 1987 May;61(5):1318–1324. doi: 10.1128/jvi.61.5.1318-1324.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Lieberman H. M., Tung W. W., Shafritz D. A. Splenic replication of hepatitis B virus in the chimpanzee chronic carrier. J Med Virol. 1987 Apr;21(4):347–359. doi: 10.1002/jmv.1890210407. [DOI] [PubMed] [Google Scholar]
  8. Rajagopalan P., Boudinot F. D., Chu C. K., Tennant B. C., Baldwin B. H., Schinazi R. F. Pharmacokinetics of (-)-2'-3'-dideoxy-3'-thiacytidine in woodchucks. Antimicrob Agents Chemother. 1996 Mar;40(3):642–645. doi: 10.1128/aac.40.3.642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Shanmuganathan K., Koudriakova T., Nampalli S., Du J., Gallo J. M., Schinazi R. F., Chu C. K. Enhanced brain delivery of an anti-HIV nucleoside 2'-F-ara-ddI by xanthine oxidase mediated biotransformation. J Med Chem. 1994 Mar 18;37(6):821–827. doi: 10.1021/jm00032a017. [DOI] [PubMed] [Google Scholar]
  11. Shimoda T., Shikata T., Karasawa T., Tsukagoshi S., Yoshimura M., Sakurai I. Light microscopic localization of hepatitis B virus antigens in the human pancreas. Possibility of multiplication of hepatitis B virus in the human pancreas. Gastroenterology. 1981 Dec;81(6):998–1005. [PubMed] [Google Scholar]
  12. Summers J., Smolec J. M., Snyder R. A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4533–4537. doi: 10.1073/pnas.75.9.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Prog Med Virol. 1978;24:40–69. [PubMed] [Google Scholar]
  14. Werner B. G., Smolec J. M., Snyder R., Summers J. Serological relationship of woodchuck hepatitis virus to human hepatitis B virus. J Virol. 1979 Oct;32(1):314–322. doi: 10.1128/jvi.32.1.314-322.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Wright J. D., Ma T., Chu C. K., Boudinot F. D. Discontinuous oral absorption pharmacokinetic model and bioavailability of 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU) in rats. Biopharm Drug Dispos. 1996 Apr;17(3):197–207. doi: 10.1002/(SICI)1099-081X(199604)17:3<197::AID-BDD948>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  16. Wright J. D., Ma T., Chu C. K., Boudinot F. D. Pharmacokinetics of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (L-FMAU) in rats. Pharm Res. 1995 Sep;12(9):1350–1353. doi: 10.1023/a:1016234009624. [DOI] [PubMed] [Google Scholar]
  17. Yeh K. C., Kwan K. C. A comparison of numerical integrating algorithms by trapezoidal, Lagrange, and spline approximation. J Pharmacokinet Biopharm. 1978 Feb;6(1):79–98. doi: 10.1007/BF01066064. [DOI] [PubMed] [Google Scholar]

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