Arabinosyl-5-azacytosine: plasma kinetics and therapeutic response (L1210) in vitro and in vivo in mice

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Abstract
Arabinosyl-5-azacytosine (Ara-AC) was studied in vitro and in vivo in kinetic and therapeutic experiments. This compound is degraded fairly rapidly in mouse plasma in vitro at 37°C (t 1/2 = 130 min) and even more rapidly in vivo (terminal t 1/2 = 76 mins, with a three phase plasma clearance curve, single dose iv 200 mg/kg). In vitro clonogenic assays with L1210 exposed to Ara-AC indicated that cytotoxic concentrations of 1 to 10 μg/ml were optimal at exposure times of 72 hours or longer (3 to 4 logs of L1210 cell kill). Extrapolating this information to in vivo infusion therapeutic studies in mice illustrated that optimal therapy (estimated 8 logs of L1210 cell kill) was also achieved at plasma concentrations of between 1 to 10 μg/ml for 72 hours of infusion. Infusions of 96 hours resulted in some lethal toxicity and 144 hour infusions were 100% lethal.