The Drug-Drug Interactions Potential Of Entacapone And Tolcapone Via Inhibition Of UDP-glucuronosyltransferases

ObjectiveThe purpose of this paper was to investigate and compare the inhibitory effects of entacapone and tolcapone on the catalytic activities of 12 kinds of human UGTs.And in vitro and in vivo extrapolation(IV-IVE)assessment was used to predicte the potential risks of drug–drug interactions(DDI)caused by entacapone and tolcapone and illustrated the liver toxicity caused by tolcapone.Methods12 kinds of human UGTs and 25 mixed human liver microsomes(HLM)were used as the enzyme-sources to characterize the inhibitory effects of tolcapone and entacapone against UGTs.Substrates,including NCHN and bilirubin for UGT1A1,trifluoperazine for UGT1A4,Propofol for UGT1A9 and 4-MU for all UGTs except UGT1A4 were selected.The half maximal inhibitory concentration(IC50)values and inhibition kinetic parametersthe(Ki)values were extrapolated and calculated from fitted curves using Graphpad Prism 6.0(San Diego,CA,USA).Dixon and Lineweaver-Burk plots were carried out to determine the reversible inhibitory type.Furthermore,the potential DDI risks and the exposure of bilirubin were also quantitatively predicted and compared by area under the curve(AUC)ratios.Results The results demonstrated that tolcapone and entacapone exhibitea wide range of inhibitory effect against not only UGT1A1 but also UGT1A7,UGT1A9,UGT1A10.The final concentration of entacapone and tolcapone was set at 100 μmol·L-1,the residual activities of UGT1A1,UGT1A7,UGT1A9 and UGT1A10 belowed 35% of their null control groups.The IC50 and Ki values were ranged from 0.98 μmol·L-1 to 14.38 μmol·L-1 and 1.40 μmol·L-1 to 19.81 μmol·L-1,respectively.After oral tolcapone 200 mg·d-1,it may result in at least a 235% increase in the AUC of bilirubin in body,and the AUC would increas 62%~249% after co-administration with other drugs metabolismed by UGT1A1,UGT1A7,UGT1A9 and UGT1A10,the values of [I]/Ki were greater than 1.In sharp contrast,the AUC of entacapone only increased by 1% at the same dose for bilirubin-O-glucuronidation,and the AUC increased 2%~14% for the drugs metabolismed by UGT1A1,UGT1A7,UGT1A9 and UGT1A10.In addition to the UGT1A7,The values of [I]/Ki for UGT1A1,UGT1A9 and UGT1A10 were less than 1.ConclusionsThe inhibitory effects of entacapone and tolcapone against UGT1A1,UGT1A7,UGT1A9 and UGT1A10 may lead to the metabolic disorder for drugs which are eliminated by UGTs.Fourthermore,both empirical methods and AUC prediction results indicated that the inhibitory effects of tolcapone against UGT1A1,UGT1A7,UGT1A9 and UGT1A10 may induce serious DDI.At the same time,the inhibitotr effects of tolcapone against UGT1A1 is likely to causes the disorder of bilirubin.Contrary,for UGT1A1,UGT1A7,UGT1A9 and UGT1A10,entacapone just showed moderate inhibition,the IV-IVE prediction results showed that the DDI risk of entacapone demonstrated to be lower and more security comparied with tolcapone,and the DDI risk casued by entacapone may reduced.Our findings provide new insights in the mechanism underlying clinically significant DDI associated with tolcapone,and also play an important roal in guding safe and rational drug use.