PT  - JOURNAL ARTICLE
AU  - Komatsu, Kanji
AU  - Ito, Kiyomi
AU  - Nakajima, Yukiko
AU  - Kanamitsu, Shin-ichi
AU  - Imaoka, Susumu
AU  - Funae, Yoshihiko
AU  - Green, Carol E.
AU  - Tyson, Charles A.
AU  - Shimada, Noriaki
AU  - Sugiyama, Yuichi
TI  - Prediction of in Vivo Drug-Drug Interactions between Tolbutamide and Various Sulfonamides in Humans Based on in Vitro Experiments
DP  - 2000 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 475--481
VI  - 28
IP  - 4
4099  - http://dmd.aspetjournals.org/content/28/4/475.short
4100  - http://dmd.aspetjournals.org/content/28/4/475.full
SO  - Drug Metab Dispos2000 Apr 01; 28
AB  - 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 (Ki) 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. TheKi 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 Ki 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. The American Society for Pharmacology and Experimental Therapeutics