TIME COURSE DIFFERENCES IN THE METABOLISM OF DRUGS BY HEPATIC MICROSOsIES FROM RATS, RABBITS AND MICE’

GRAM, THEODORE E. AND JAMES R. FouTs: Time course differences in the metabolism of (hugs by hepatic microsornes from rats, rabbits and mice. J. Pharmac. Cxl). Ther. 152: 363-371, 1966. In t’itio time course stutlies of the metal)olism of hexobarbital, codeine, zoxazolamine, p-nitrobenzoic acid, Xeoprontosil, aminopyrine and benzpyrcne have been carried out by employing hpatic microsomes from rabbits, rats and mice. In general, rela-tivelv early deviation from linear metabolism was observed with rat liver microsomes; with some substrates, this occurred in less than 15 nun. In several cases with rat liver, early plateaus in drug metabolic activity occurred, with no further metabolism of drugs beyond 45 or 60 mm of incubation. By contrast, rabbit and mouse liver microsomes metal)olized drugs linearly with time for considerably longer periods, 60 to 90 mm in some cases. The early departure from linearity seen with rat liver microsomes was not influenced by dou-bling substrate concentrations, doubling cofactor concentrations or addition of excess re-duced nicotinamide adenine dinucleotide phosphate. Similarly, it did not seem to be the result of produ(’t inhibition or of inactivation of cytochrome P-450. The period of linea