Metabolism of 1-phthalidyl 5-fluorouracil in rat liver and enzyme induction by phenobarbital

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Abstract
1. When 1-phthalidyl 5-fluorouracil (PH-FU) was incubated with isolated rat hepatocytes, 5-fluorouracil, 2-carboxybenzaldehyde (CBA) and .alpha.-hydroxymethylbenzoic acid (HMB) were detected as the major metabolites. 2. The enzymes involved in the metabolism of PH-FU, PH-FU hydrolase and CBA reductase are cytosolic and were induced by treating the rats with phenobarbital (PB). 3. The PB-induced PH-FU hydrolase was inhibited by NADH and several aldehydes, while NAD stimulated the hydrolase and protected it from inactivation by SH reagents. 4. Study in vivo revealed that treatment of rats with PB accelerated the metabolism of PH-FU in the liver and markedly decreased the blood PH-FU after its oral administration to rats, which resulted in reduction of the anti-tumor activity of PH-FU. This activity was not affected by treatment of the rats with 3-MC.