Elsevier

Biochemical Pharmacology

Volume 30, Issue 24, 15 December 1981, Pages 3347-3354
Biochemical Pharmacology

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

https://doi.org/10.1016/0006-2952(81)90611-0Get rights and content

Abstract

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 (CLtot) in rats. The The sulfonamides used were sulfaphenazole (SP), sulfadimethoxine (SDM) and sulfamethoxazole (SMZ). The plasma half-life (T12) of tolbutamine (TB) was increased ssignificantly by SP and SDM, while CLtot 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 vivoCLtot can be expressed by the equation; CLtot ⋍ ƒBCLint, where ƒB is the blood free fraction and CLint is the hepatic intrinsic clearance of unbound drug. A comparatively good agreement was observed between the in vivoCLtot and that calculated from both in vitro plasma protein binding and metabolic parameters.

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    This study was supported by a grant-in-aid for Scientific Research provided by the Ministry of Education.

    Author to whom all correspondence should be addressed.

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