Prediction of drug-drug interaction from In vitro plasma protein binding and metabolism: A study of tolbutamide-sulfonamide interaction in rats

The prediction of tolbutamide-sulfonamide interaction from in vitro unbound intrinsic clearance was studied by comparing the in vvivo and in vitro total body clearance (CL_tot) in rats. The The sulfonamides used were sulfaphenazole (SP), sulfadimethoxine (SDM) and sulfamethoxazole (SMZ). The plasma half-life (T_1/2) of tolbutamine (TB) was increased ssignificantly by SP and SDM, while CL_tot was decreased significantly by both drugs; no significant changes were observed in their parameter by SMZ. The in vitro plasma protein binding and microsomal oxidation of TB were competitively inhibited by sulfonamides; the order of inhibitor constantswas SMZ>SP>SDM. Since metabolism is the rate-determining step of the hepatic extraction of TB, the in vivo CL_tot can be expressed by the equation; CL_tot ƒ_BCL_int, where ƒ_B is the blood free fraction and CL_int is the hepatic intrinsic clearance of unbound drug. A comparatively good agreement was observed between the in vivo CL_tot and that calculated from both in vitro plasma protein binding and metabolic parameters.