Vol. 28, Issue 4, 475-481, April 2000

Prediction of in Vivo Drug-Drug Interactions between Tolbutamide and Various Sulfonamides in Humans Based on in Vitro Experiments

Kanji Komatsu, Kiyomi Ito, Yukiko Nakajima, Shin-ichi Kanamitsu, Susumu Imaoka, Yoshihiko Funae, Carol E. Green, Charles A. Tyson, Noriaki Shimada, and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.K., Y.N., S.K., Y.S.); School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (K.I.); Laboratory of Chemistry, Osaka City University Medical School, Osaka, Japan (S.I., Y.F.); Toxicology Laboratory, SRI International, Menlo Park, California (C.E.G., C.A.T.); Research and Development Division, Daiichi Pure Chemicals Co., Ltd., Osaka, Japan (N.S.)

Drug-drug interactions between tolbutamide and sulfonamides have extensively been reported. We attempted to predict the in vivo interaction between tolbutamide and sulfonamides from the in vitro metabolic inhibition studies. The inhibition constant (K_i) was derived from the inhibitory effects of eight sulfonamides (sulfaphenazole, sulfadiazine, sulfamethizole, sulfisoxazole, sulfamethoxazole, sulfapyridine, sulfadimethoxine, and sulfamonomethoxine) on tolbutamide metabolism. We found that the inhibitory effect of sulfaphenazole was greatest among the eight sulfonamides examined. Furthermore, the contribution of each P450 enzyme to tolbutamide metabolism was investigated by using recombinant P450 enzymes. Although cytochrome P450 (CYP) 2C8, 2C9, and 2C19 metabolized tolbutamide, the main enzyme involved was CYP2C9. The K_i values of several sulfonamides were comparable between human liver microsomes and recombinant CYP2C9. The maximum unbound plasma concentration of sulfonamides in the portal vein was calculated from literature data on the pharmacokinetics of sulfonamides. Using the K_i values obtained from in vitro inhibition studies, the degree of increase in tolbutamide area under the plasma concentration-time curve (AUC) was predicted. About 4.8- and 1.6-fold increases in tolbutamide AUC were predicted by coadministration of sulfaphenazole and sulfamethizole, respectively, which agreed well with the reported increases in humans. Furthermore, the increase in tolbutamide AUC by coadministration of sulfadiazine, sulfisoxazole, and sulfamethizole was predicted to be 1.5- to 2.6-fold, although the corresponding in vivo effects have not been reported. It is concluded that some of these sulfonamides have to be carefully coadministered with CYP2C9 substrates such as tolbutamide although coadministration of sulfaphenazole needs the greatest care.