1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU), the L isomer of FMAU, has shown potent activity against hepatitis B virus and Epstein-Barr virus. L-FMAU showed double peaks in the plasma concentration versus time profiles following oral administration to rats, indicating discontinuous oral absorption. The objective of this study was to characterize the bioavailability and pattern of L-FMAU absorption using a pharmacokinetic model which incorporated two separate absorption processes following oral administration of the nucleoside in an animal model, the rat. Simultaneous fitting of differential equations to L-FMAU plasma concentrations following oral and intravenous administration was performed using PCNONLIN. Total clearance of L-FMAU was moderate, averaging 0.47 +/- 0.16 L h-1 (mean +/- SD). Distributional clearance averaged 0.18 +/- 0.14 L h-1. The volume of the central compartment averaged 0.30 +/- 0.09 L, and the volume of the peripheral compartment averaged 0.15 +/- 0.08 L. The first-order absorption rate constants describing the first and second absorption phases averaged 1.22 +/- 1.56 and 4.14 +/- 5.42 h-1, respectively. Oral bioavailability was calculated by three methods: AUC, urinary excretion data, and a discontinuous oral absorption pharmacokinetic model. Bioavailability averaged 0.59 +/- 0.16, 0.64 +/- 0.23, and 0.63 +/- 0.13, respectively, for the three methods. The discontinuous oral absorption pharmacokinetic model is a promising new method for estimating absorption from two phases and for calculating oral bioavailability.