Inhibition of human liver microsomal CYP by nateglinide

Abstract

Nateglinide is metabolized by CYP2C9 and CYP3A4, therefore drug-drug interactions through cytochrome P450 (CYP) inhibition may occur. In this study, we examined the inhibitory effects of nateglinide and its major metabolite N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine (M1) on various CYP isoforms in human liver microsomes. We used typical substrates (7-ethoxyresorufin for CYP1A1/2, tolbutamide for CYP2C9, S-mephenytoin for CYP2C19, bufuralol for CYP2D6, chlorzoxazone for CYP2E1 and midazolam for CYP3A4) in the evaluation of the inhibitory effects, and examined the possibility of mechanism-based inhibition (MBI) by evaluating the influence of pre-incubation in the inhibition. The results showed that nateglinide inhibited CYP2C9 and CYP2C19 with an IC50(app) (apparent value of the 50% inhibitory concentration) of 125 micromol/l and 946 micromol/l, respectively, while M1 did not inhibit any of the CYP isoforms. The inhibition constant (K(i)) value of the inhibitory effect of nateglinide on CYP2C9 and the 1 + I(in,max,u)/K(i) value were estimated (where I(in,max,u)= the maximum unbound concentration of nateglinide). The 1 + I(in,max,u)/K(i) value was 1.02 (close to 1), suggesting a low risk of drug-drug interactions. The influence of pre-incubation on the inhibition by nateglinide of CYP3A4, CYP2C9 and CYP2C19 was examined. The results revealed that the inhibition of CYP by nateglinide was not influenced by pre-incubation, and that the possibility of MBI is very low. The possibility of drug-drug interactions involving nateglinide that might be attributable to CYP inhibition is low.