LIVER DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY IN HUMAN, CYNOMOLGUS MONKEY, RHESUS-MONKEY, DOG, RAT AND MOUSE

Interspecies differences in dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme in pyrimidine degradation, were asse ssed in cytosol from livers isolated from human, monkey, dog, rat, and mouse. Hepatic DPD activity was measured by an HPLC assay with on-lin e radioactivity detection, using C-14-5-fluorouracil as a substrate. A ctivity was highly variable within each species and significant inters pecies differences in liver DPD activity were observed. The order of a ctivity was mouse > rat > human > dog greater than or equal to cynomol gus monkey > rhesus monkey. These data suggest that careful selection must be made when choosing in vivo models of human DPD for the preclin ical development of novel fluoropyrimidine anticancer agents and DPD i nhibitors.