Pharmacokinetics of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (L-FMAU) in rats.
OBJECTIVE
The objective of this study was to characterize the pharmacokinetics of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (L-FMAU), a nucleoside analogue with potent activity against the hepatitis B virus and the Epstein-Barr virus, in rats.


METHODS
Three doses of L-FMAU were administered intravenously (10, 25, and 50 mg/kg) to rats, and L-FMAU concentrations in plasma and urine were measured by HPLC. Pharmacokinetic parameters were generated by using area-moment analysis.


RESULTS
There were no significant differences in the pharmacokinetic parameters between the three doses (alpha < 0.05). Thus, the disposition of L-FMAU was linear over the dosage of 10 to 50 mg/kg. Plasma concentrations of L-FMAU declined rapidly with a terminal phase half-life of 1.33 +/- 0.45 h (mean +/- SD). Total clearance of L-FMAU was moderate, averaging 1.15 +/- 0.28 L/h/kg. The fraction of compound excreted unchanged in urine was 0.59 +/- 0.13. No glucuronide metabolite was found in the urine. The steady-state volume of distribution was 1.12 +/- 0.26 L/kg indicating intracellular distribution of the compound. The fraction of L-FMAU bound to plasma proteins was approximately 15% and was independent of nucleoside concentration.


CONCLUSIONS
The pharmacokinetics of L-FMAU in rats were independent of dose over the dosage range of 10 to 50 mg/kg.
Wright
J D
JD
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602, USA.
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Boudinot
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D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C034935:clevudine