Pharmacokinetics of 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rats.

Although several drugs have shown clinical anti-human immunodeficiency virus activity, reduced activity with long-term use and toxicity make new agents with high therapeutic indices desirable. Racemic cis-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) is a new synthetic nucleoside analogue that is usually potent against human immunodeficiency virus types 1 and 2 and hepatitis B virus in vitro. The purpose of this study was to characterize the preclinical pharmacokinetics of FTC in rats. Rats were administered 10, 50, and 100 mg of FTC per kg of body weight intravenously. Concentrations of FTC in plasma and urine were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma FTC concentrations declined rapidly in a biexponential fashion, with a terminal half-life of approximately 2 h. The area under the plasma FTC concentration-time curve increased proportionally with increasing dose, and there were no statistically significant differences in pharmacokinetic parameters among the three doses. Thus, the disposition of FTC was independent of dose over the range of 10-100 mg/kg. Since the disposition of FTC was linear, pharmacokinetic parameters were averaged for the three doses. The average total clearance of FTC was 1.91 +/- 0.32 L/h/kg (mean +/- SD), the average renal clearance was 1.08 +/- 0.26 L/h/kg, and the average nonrenal clearance was 0.83 +/- 0.27 L/h/kg. Approximately 55% of the dose of FTC was recovered as unchanged drug in the urine. The steady-state volume of distribution of FTC averaged 2.17 +/- 0.59 L/kg.

[1]  H. McClure,et al.  Pharmacokinetics and metabolism of racemic 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rhesus monkeys , 1992, Antimicrobial Agents and Chemotherapy.

[2]  R F Schinazi,et al.  Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine , 1992, Antimicrobial Agents and Chemotherapy.

[3]  B. Larder,et al.  Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Cameron,et al.  The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro , 1992, Antimicrobial Agents and Chemotherapy.

[5]  R. Schinazi,et al.  In situ complexation directs the stereochemistry of N-glycosylation in the synthesis of oxathiolanyl and dioxolanyl nucleoside analogues , 1991 .

[6]  S D Kemp,et al.  Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. , 1991, Science.

[7]  R. Schinazi,et al.  Pharmacokinetics of 3′-azido-2′,3′-dideoxy-5-methylcytidine in Rats , 1990 .

[8]  H. McClure,et al.  Antiretroviral Activity, Biochemistry, and Pharmacokinetics of 3′‐Azido‐2′,3′‐Dideoxy‐5‐Methylcytidine a , 1990, Annals of the New York Academy of Sciences.

[9]  F. Douglas Boudinot,et al.  Pharmacokinetics of 2′,3′‐Dideoxycytidine in Rats: Application to Interspecies Scale‐up , 1989, The Journal of pharmacy and pharmacology.

[10]  C. K. Chu,et al.  Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats. , 1989, Journal of pharmaceutical sciences.

[11]  H. Langtry,et al.  Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. , 1989, Drugs.

[12]  D. Richman,et al.  HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. , 1989, Science.

[13]  J. A. Nelson,et al.  Renal transepithelial transport of nucleosides. , 1988, Drug metabolism and disposition: the biological fate of chemicals.

[14]  D. Vistica,et al.  The disposition and metabolism of 2',3'-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[15]  M A Fischl,et al.  The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. , 1987, The New England journal of medicine.

[16]  E. Gelmann,et al.  ADMINISTRATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE, AN INHIBITOR OF HTLV-III/LAV REPLICATION, TO PATIENTS WITH AIDS OR AIDS-RELATED COMPLEX , 1986, The Lancet.

[17]  T. Lin,et al.  Synthesis and biological activity of various 3'-azido and 3'-amino analogues of 5-substituted pyrimidine deoxyribonucleosides. , 1983, Journal of medicinal chemistry.

[18]  R K Jain,et al.  Physiologically based pharmacokinetic modeling: principles and applications. , 1983, Journal of pharmaceutical sciences.

[19]  W J Jusko,et al.  LAGRAN program for area and moments in pharmacokinetic analysis. , 1983, Computer programs in biomedicine.

[20]  C M Metzler,et al.  Bioavailability--a problem in equivalence. , 1974, Biometrics.

[21]  C. G. Smith,et al.  Studies of the enzymatic deamination of cytosine arabinoside. I. Enzyme distribution and species specificity. , 1967, Biochemical pharmacology.

[22]  B. Larder,et al.  Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. , 1992, The Journal of infectious diseases.