Abstract
4-[14C]Ethynylbiphenyl has been synthesised and its metabolism studied in the rat and the rabbit. 4'-Hydroxy-4-biphenylylacetic acid and 4-phenylmandelic acid were synthesised for use as standards to aid identification of metabolites. When 4- [14C] ethynylbiphenyl was dosed orally to rats and rabbits (40 mg/kg) no unchanged parent drug was excreted in the urine or faeces. The excretion of radioactivity was more rapid in the rabbit than the rat (72% after 24h compared to 52%). The excretion time in the rat was longer than in the rabbit. The prolonged excretion observed in the rat together with significant amounts of radioactivity appearing in the faeces suggested that biliary excretion and enterohepatic circulation occurs in this species. This has been confirmed in rats fitted with bile-duct cannulae. Enterohepatic circulation was greatly diminished by pretreatment with 1,4-saccharo-lactone or with antibiotics. The major metabolite excreted by the rat and the rabbit was 4'-hydroxy-4-biphenylylacetic acid. 4-Biphenylylacetic acid was found to be the secondary metabolite in both species (0-2% in the rat, 2-4% in the rabbit). 4-Phenylmandelic acid and 4-acetyl biphenyl were found as trace metabolites. The identities of these metabolites were confirmed by mass-spectroscopy and n.m.r. The major metabolite, 4'-hydroxy-4-biphenylylacetic acid has been shown to be inactive as an inhibitor of prostaglandin synthetase {in vitro) whereas 4-biphenylylacetic acid exhibited moderate activity. Metabolism of 4-ethynylbiphenyl was studied in rat liver sub-cellular fractions, both normal and induced with phenobarbitone or 3-methylcholanthrene. The major metabolite observed was 4-biphenylylacetic acid and the metabolism of 4-ethynylbiphenyl, or more specifically the acetylene group, was greatly induced by both phenobarbi tone and 3-methylcholanthrene. A mechanism is proposed to account for this novel metabolic transformation.