Pharmacology and Toxicology of a Seven-Day Infusion of 1-/Ì-D-Ara binof ura nosy Icy tosi ne plus Uridine in Dogs1

In vitro studies of certain lymphoid tumor cells show potentiation of 1-/3-o-arabinofuranosylcytosine (ara-C) effects by undine because it elevates intracellular undine triphosphate, resulting in increased ara-C triphosphate levels. Seven-day continuous i.v. infusions of undine at 123 mg/kg/h (2.5 g/sq m/h) were studied in 5 male beagles. Steady state levels of undine were reached within 4 to 6 h and ranged from 2 to 5 x 10"4 M over the course of the infusion. Steady state uracil levels ranged from 4 to 10 x 10"4 M. After the end of infusion, undine and uracil levels fell with a half-life of approximately 15 and 18 min, respectively. Toxicity in 2 dogs treated at this dose was limited to minimal diarrhea and a transient rise of alkaline phosphatase to 2 to 3 times normal. No drug toxicity was evident at sacrifice on Days 7 or 72. Three dogs received a 7-day infusion of ara-C plus uridine followed approximately 4 weeks later by an infusion of ara-C alone (or the same drugs in the reverse sequence). Coinfusion of 2.5 or 5.0 mg/kg/day (50 or 100 mg/sq m/day) of ara-C had no significant effects on uridine plasma levels or postinfusion half-lives. Similarly, no consistent effect was seen of uridine on ara-C plasma levels. Uridine coinfusion with ara-C resulted in a definite potentiation of myelosuppression; at 5.0 mg/kg/day x 7 of ara-C white blood cell and platelet nadirs (x IO3//*!) were 0.8 and 15 as compared to 3.6 and 66, respectively, with ara-C alone. One-third of the dogs developed reversibly elevated transaminases with the combination treatment. The results show that a minimally toxic dose of uridine enhances bone marrow and probably hepatic toxicity of coadministered ara-C.