DISCONTINUOUS ORAL ABSORPTION PHARMACOKINETIC MODEL AND BIOAVAILABILITY OF -(2-FLUORO-5-METHYL-BETA-L-ARABINOFURANOSYL)URACIL (L-FMAU) IN RATS

1-(2-fluoro-5-methyl-beta-L-arabinofuranosy (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 ver sus time profiles following oral administration to rats, indicating di scontinuous oral absorption. The objective of this study was to charac terize the bioavailability and pattern of L-FMAU absorption using a ph armacokinetic model which incorporated two separate absorption process es following oral administration of the nucleoside in an animal model, the rat. Simultaneous fitting of differential equations to L-FMAU pla sma concentrations following oral and intravenous administration was p erformed using PCNONLIN. Total clearance of L-FMAU was moderate, avera ging 0.47 +/- 0.16 L h(-1) (mean+/-SD). Distributional clearance avera ged 0.18 +/- 0.14 L h(-1). The volume of the central compartment avera ged 0.30 +/- 0.09 L, and the volume of the peripheral compartment aver aged 0.15 +/- 0.08 L. The first-order absorption rate constants descri bing the first and second absorption phases averaged 1.22 +/- 1.56 and 4.14 +/- 5.42 h(-1), respectively. Oral bioavailability was calculate d by three methods: AUC, urinary excretion data, and a discontinuous o ral 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.