Abstract
Serious side-effects caused by drug interactions have become asocial problem since an interaction between sorivudine and 5-fluorouracil (5-FU) resulted in a number of deaths due to toxicity in Japan. This interaction has been found to result from mechanism-based inhibition of dihydropyrimidine dehydrogenase (DPD) which is involved in 5-FU metabolism. A mechanism-based inhibitor is one that is metabolized by an enzyme to form a metabolite which covalently binds to the same enzyme, leading to irreversible inactivation of the enzyme. In this study, we have predicted 5-FU /sorivudine and triazolam/erythromycin interactions from in vitro studies by considerating the mechanism-based inhibition of DPD and CYP3A, respectively.
Human hepatic enzyme was preincubated with the inhibitor in the presence of NADPH and the remaining metabolic activity was evaluated. The inhibitory effects of (E)-5-(2-bromovinyl)uracil (a metabolite of sorivudine) and erythromycin were found to depend on both the preincubation time and inhibitor concentration. Time-courses of 5-FU and triazolam concentrations in blood were simulated by a physiologically-based pharmacokinetic (PBPK) model, using in vitro kinetic parameters for the enzyme inactivation and pharmacokinetic parameters reported in the literature. The predicted AUC ratio of triazolam in the presence and absence of erythromycin was consistent with the AUC ratio actually observed in vivo. The AUC of 5-FU was predicted to be increased more than 5-fold by sorivudine, indicating that coadministration of these drugs is very dangerous.
