AntitumorEffectsand Pharmacology of OrallyAdministered N4-Palmitoyl I -fi-D-arabinofuranosylcytosine in Mice1

ABSTRACTThe antitumoractivityand the pharmacolOgicalfate of N4-palmitoyl-1-fi-D-arabinofuranosylcytosine(N@-palmftoyI-ara-C) administered p.o. were examined in mice and were compared withthoseoftheparentcompound1-@9-o-arabinofuranosyicyto sine (era-C).N@-Palmitoyl-ara-Cadministered p.o. showed themotherapeutic effects superior to those of ara-Cwhen usedagainst P388 leukemia, Li 210 leukemia, mammary adenocarci noma755, andcolon38 adenocarcinoma.Thederivativealso inhibited the spontaneous pulmonary metastasis of s.c.-inoculated Lewis lung carcinoma more efficiently than did era-C.After asinglep.o.injectionofasuspensionofN@-paImitoyl-[2-14C]ara C at a therapeuticdoseof 350 ,anol/kg,a highconcentrationof thedrugwasfoundintheliver,lung,andplasmaofportalvenousblood. The levelof the drug in other tissuesand peripheralplasmawasratherlow.Thetwo mainmetabolites,identifiedas era-Cand 1-fl-D-arabinofuranosyluracsl,were found in plasma andvarioustissues.Plasmaare-Cconcentrationwasmaintainedforat least6 hr intherangeof 2.3 to 5.1 nmol/mlafterp.o.