Prediction of in vivo drug-drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments.

Article Details

Citation

Komatsu K, Ito K, Nakajima Y, Kanamitsu Si, Imaoka S, Funae Y, Green CE, Tyson CA, Shimada N, Sugiyama Y

Prediction of in vivo drug-drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments.

Drug Metab Dispos. 2000 Apr;28(4):475-81.

PubMed ID
10725317 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
Acetyl sulfisoxazoleCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SulfadiazineCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SulfadimethoxineCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SulfamethizoleCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SulfapyridineCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SulfisoxazoleCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
TolbutamideCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details
TolbutamideCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Inhibitor
Details