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Antimicrobial Agents and Chemotherapy, June 2003, p. 1922-1928, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1922-1928.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antiviral Activity and Pharmacokinetics of 1-(2,3-Dideoxy-2-Fluoro-ß-L-Glyceropent-2-Enofuranosyl)Cytosine

Huachun Chen,1,2 S. Balakrishna Pai,2 Selwyn J. Hurwitz,1,2 Chung K. Chu,3 Yuliya Glazkova,1,2 Harold M. McClure,4 Mark Feitelson,5 and Raymond F. Schinazi1,2,4,6*

Department of Pediatrics,1 Center for AIDS Research,6 Yerkes National Primate Research Center, Emory University,4 Veterans Affairs Medical Center, Decatur, Georgia 30033,2 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602,3 Thomas Jefferson University, Philadelphia, Pennsylvania 19107-67995

Received 6 September 2002/ Returned for modification 18 November 2002/ Accepted 26 February 2003

1-(2,3-Dideoxy-2-fluoro-ß-L-glyceropent-2-enofuranosyl)cytosine (L-2'-Fd4C) is an L-nucleoside analogue with both anti-human immunodeficiency virus (HIV) and anti-hepatitis B virus (HBV) activity with median effective concentrations of 0.12 µM in peripheral blood mononuclear cells and 0.002 µM in HepG2-2.2.15 cells, respectively. The purpose of this study was to examine the antihepadnavirus potency and pharmacokinetics of L-2'-Fd4C in vivo. HBV-transgenic mice treated intraperitoneally with L-2'-Fd4C showed a reduction of HBV levels in their blood comparable to that produced by lamivudine. The pharmacokinetics of L-2'-Fd4C in rhesus monkeys was evaluated after intravenous and oral administration. The concentrations in plasma declined in a biexponential manner after intravenous administration, with a long terminal-phase half-life of 5.02 h. The steady-state volumes of distribution and systemic clearance were 1.09 liter · kg-1 and 0.25 liter · h-1 · kg-1, respectively, with a renal clearance of 0.16 liter · h-1 · kg-1. The oral bioavailability was approximately 44%. About 53% of the compound administered intravenously and 19% of that administered orally were recovered unchanged in the urine within the 24-h urine collection period, and no other metabolite was detected. The compound penetrated the central nervous system at concentrations that exceeded the median effective antiviral concentration against HIV in cell cultures. Based upon these observations, further testing to develop this agent for treatment of HIV and HBV infections is warranted.

* Corresponding author. Mailing address: Veterans Affairs Medical Center, Medical Research 151H, 1670 Clairmont Rd., Decatur, GA 30033. Phone: (404) 728-7711. Fax: (404) 728-7726. E-mail: rschina{at}emory.edu.

Antimicrobial Agents and Chemotherapy, June 2003, p. 1922-1928, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1922-1928.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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