Displacing effects of chenodeoxycholic acid, ursodeoxycholic acid and sulfadimethoxine on plasma protein binding of tolbutamide.

The interactions between chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) and tolbutamide including its displacement from plasma protein binding sites were investigated pharmacokinetically. An increasing concentration of unbound tolbutamide was observed in the in vitro experiment, conducted by equilibrium dialysis method at 30 degrees C after the addition of CDCA and UDCA to human serum albumin (HSA), bovine serum albumin (BSA) and rabbit plasma containing tolbutamide. Small changes in total plasma concentration of tolbutamide were noted after high dose (0.167 mg/kg/min) intravenous infusion of CDCA to rabbits receiving a constant intravenous infusion of tolbutamide, but, such an observation was not obtained with low dose (0.083 mg/kg/min) of CDCA or with either high or low dose of UDCA. These results seem to indicate the displacement of high doses of CDCA. The coadministration of sulfadimethoxine which not only displaces tolbutamide from binding sites but also inhibits its metabolism was investigated. A different plasma pattern was obtained under the same intravenous infusion conditions, as compared with the plasma pattern resulting from tolbutamide-CDCA or UDCA combination.