PHYSIOLOGIC DISPOSITION OF 4', 4''-BIS(1,4,5,6-TETRAHYDRO-2-PYRIMIDINYL)TEREPHTHALANILIDE AND 4-(1,4,5,6-TETRAHYDRO-2-PYRIMIDINYL)-4'-[p-(1,4,5,6-TETRAHYDRO-2-PYRIMIDINYL)PHENYL]CARBAMOYLBENZANILIDE IN DOGS, MONKEYS, RATS AND MICE

¹ Life Sciences Division, Arthur D. Little, Inc., Cambridge, Massachusetts
² Life Sciences Division, Arthur D. Little, inc., Cambridge, Massachusetts

Salient features of the physiologic disposition in animals of two orally active phthalamlide congeners were determined for comparison to the disposition of others which are not active against murine lymphocytic leukemias when administered orally, but which are highly active when administered intraperitoneally or intramuscularly. Drug concentrations were determined mostly by spectrophotometry after direct chromatographic isolation from tissues and fluids or by acid displacement from specific complexes with phospholipids. A small fraction of drug was absorbed after oral administration to fasted rats, mice, dogs and monkeys. The pattern of distribution of drug in tissues was similar after oral or intravenous administration. Kidneys had the highest drug concentration. Neither drug could be detected in the blood 24 hr after injections. About 30% of each daily intravenous dose of 4-(1,4,5,6-tetrahydro-2-pyrimidinyl)-4'-[p-(l,4,5,6-tetrahydro-2-pyrimidinyl)phenyl]carbamoylbenzanilide and 15 to 20% of each daily dose of 4', 4''-bis(1,4,5,6-tetrahydro-2-pyrimidinyl)terephthalanilide was excreted in the urine. There was no evidence of metabolites which contained primary aromatic amines after strong acid hydrolysis.