CORRELATION OF C-14 GRISEOFULVIN METABOLISM IN RAT-LIVER MICROSOMES, ISOLATED PERFUSED RAT LIVERS, AND IN RATS WITH BILE-DUCT CANNULAS

Abstract

The metabolism of 14C-griseofulvin was compared in rat liver microsomes, isolated perfused rat livers and rats with bile duct cannulas. In all 3 preparations, 4-desmethylgriseofulvin and 6-desmethylgriseofulvin were the major metabolites. The ratio of total 4-desmethylgriseofulvin to 6-desmethylgriseofulvin formed was 1.20, 0.89 and 1.01 in liver microsomes, isolated perfused livers and rats with bile duct cannules, respectively. After a 7-min incubation with liver microsomes, most (96%) of the griseofulvin remained unchanged. Only small amounts of 4-desmethylgriseofulvin (1.26% of dose) and 6-desmethylgriseofulvin (1.05% of dose) were formed. In isolated perfused liver, most of the drug (59% of dose) was excreted into bile within 4 h, primarily as 4-desmethylgriseofulvin (24% of dose) and 6-desmethylgriseofulvin (24% of dose). In animals with bile duct cannules, 65% of the dose was excreted into bile and 18% into urine within 4 h. In bile, 32% of the dose was excreted as 4-desmethylgriseofulvin and 20% as 6-desmethylgriseofulvin, whereas in urine the drug was excreted predominantly as 6-desmethylgriseofulvin (13% of dose) with only a small amount of 4-desmethylgriseofulvin (1% of dose), during the 1st 4 h. There is good correlation in the metabolic fate of 14C-griseofulvin in the liver microsomes, isolated perfused liver and rats with bile duct cannulas. In addition to the similar ratio of 4-desmethylgriseofulvin to 6-desmethylgriseofulvin, there is also an agreement in the extent of metabolism and biliary excretion in isolated perfused liver and in rats with bile duct cannulas, which suggests that the isolated perfused liver is an important technique for studying drug metabolism in animals.