1993 Volume 8 Issue 1 Pages 49-66
The metabolism of ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) was examined in rats, guinea-pigs and dogs. The binding to plasma (or serum) protein and interaction with reference drugs in binding to human serum protein were also investigated.
1. Metabolites in rats were almost all those with a hydrolized amido-bond in ONO-1078 molecule, except unchanged drug which was not absorbed and excreted into feces. Besides, metabolites in rat were quite different from those of dog. In this manner, species-difference was observed.
2. MC-0 and MH-0, hydrolized metabolites of ONO-1078, and besides MH-1 and MH-2, taurine conjugates of MH-0 and hydroxylated MH-0, respectively, were identified as main metabolites in rats. Moreover a part of MH-0 was incorporated into the adipose tissue as triglycerides.
3. Similarly to rats, the metabolite which had hydrolized amido-bond in ONO-1078 molecule was observed in guinea-pigs.
4. The amido-bond of ONO-1078 was not hydrolized in dogs. Main metabolites were M-1, as mono-hydroxylated form, M-2, as di-hydroxylated form of ONO-1078, and M-3, as sulfoconjugates of M-1 and M-2.
5. ONO-1078 was rapidly hydrolized in liver microsomal fraction obtained from rat and guinea-pig. The enzyme hydrolizing compound in rat liver was identified as carboxylesterase. But, in dog liver microsomal fraction, ONO-1078 was not hydrolized.
6. In the presence of carboxylesterase inhibitor, the formation of M-1 and M-2 in rat liver microsomal fraction was observed.
7. In vivo binding to plasma (or serum) protein after oral administration varied 97.1 ?? 98.9% in rats, 76.1 ?? 84.1% in dogs. All the binding to rat, dog and human serum proteins in vitro were more than 99.7%.
8. The examination of interaction with reference drugs in the binding to human serum protein revealed that ONO-1078 and every reference drugs tested did not affect to the binding ratio of each other.
