Drug-drug interactions of Z-338, a novel gastroprokinetic agent, with terfenadine, comparison with cisapride, and involvement of UGT1A9 and 1A8 in the human metabolism of Z-338

In the present study, the inhibitory properties of N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide monohydrochloride trihydrate (Z-338), a novel gastroprokinetic agent, were investigated and compared with those of cisapride to establish its potential for drug-drug interactions. There was no notable inhibition of terfenadine metabolism or of any of the isoforms of cytochrome P450 (CYP1A1/2, 2A6, 2136, 2C9, 2C19, 2D6, 2E1 and 3A4) by Z-338 in in vitro studies using human liver microsomes. Z-338 was mainly metabolized to its glucuronide by UGT1A9 (UDP glucoronosyltransferase I family, polypeptide A9) and UGT1A8, and did not show marked inhibition of P-glycoprotein activity. On the other hand, cisapride strongly inhibited CYP3A4 and markedly inhibited CYP2C9. Furthermore, we used the whole-cell patch-clamp technique to investigate the effects of Z-338 and cisapride on potassium currents in human embryonic kidney (HEK) 293 cells transfected with the human ether-a-go-go-related gene (hERG). Z-338 had no significant effect on hERG-related current at the relatively high concentration of 10 muM In contrast, the inhibition by Z-338 was very small compared with that of cisapride at 10 nM, which was a thousand-fold lower concentration. In the prediction method for the drug interaction between terfenadine and cisapride based on the K-i and PK parameters, we suggest the possibility that terfenadine mainly affect the QT interval, since its plasma concentration would be markedly increased, but cisapride may not be changed. Thus, in contrast with cisapride, Z-338 did not inhibit CYP and the hERG channel, and is predominantly metabolized by glucuronide conjugation, Z-338 is considered unlikely to cause significant drug-drug interactions when coadministered with CYP substrates at clinically effective doses. (C) 2004 Elsevier B.V. All rights reserved.