Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine prodrugs are increasingly being adm inistered in preference to intravenous nucleoside analogues in cancer chemo therapy, their activation in malignant liver tissue may be insufficient. OG T 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, p referentially localized in hepatocytes and hepatoma cells via the asialogly coprotein receptor. The aim of this study was to assess the systemic bioava ilability of this rationally designed drug in 16 patients with advanced sol id cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m(2)) OGT 719. Results: Linear pharmaco kinetics a nd oral bioavailability of approximately 25% were observed at the close lev els used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mea n half-life for oral doses was 4 h. OGT 719 was well tolerated. No objectiv e tumour responses were demonstrated. Conclusion: The systemic bioavailabil ity and half-life of oral OGT 719 are sufficient to merit dose escalation s tudies with frequent daily dosing. Subsequent efficacy studies should be pe rformed in patients with primary and secondary liver malignancies.