Pharmacokinetic characteristics of the cytarabine prodrug, ilecytarabine, after intravenous and oral administration to rats

Purpose: To compare the pharmacokinetics of a pyrimidine nucleoside analogue 1-β-D-arabinofuranosylcytosine (cytarabine, ara-C) with its amino acid prodrug, L-ilecytarabine, following intravenous and oral administrations to rats. Methods: The plasma concentrations were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC/MS/MS) using a new validated method. Results: When cytarabine was intravenously administered at 8 mg/kg, the area under the concentration-time profile (AUC) was 26.29±4.11 μg·h/ml, and the Cmax was 16.85±3.50 μg/ml in plasma. Then, following oral administration of ara-C and its prodrug, L-ilecytarabine, at a dose of 30 mg/kg (calculated as cytarabine), the AUC (calculated as cytarabine) after L-ilecytarabine administration was 25.55±5.41 μg·h/ml and the AUC after ara-C administration was 11.33±1.52 μg·h/ml. The Cmax (calculated as cytarabine) of L-ilecytarabine was 5.75±1.68 μg·h/ml and that of ara-C was 2.75±0.67 μg·h/ml. The relative bioavailability calculated as ara-C was 215.15%±33.67% for ilecytarabine. Conclusion: L-ilecytarabine is an oral alternative to cytarabine and this study validated the utility of the PepT1-targeted approach to improve the oral bioavailability of poorly absorbed drugs.

Keywords: L-ilecytarabine Amino acid prodrug Bioavailability PepT1