Development of in VitroVmax and K m Values for the Metabolism of Isofenphos by P-450 Liver Enzymes in Animals and Human

Abstract

The rate of metabolism of [ 14C]isofenphos (IFP) to isofenphos oxon (IFP-oxon), des N-isofenphos (d- N-IFP), and des N-isofenphos oxon (d-N-IFP-oxon) by rat, guinea pig, monkey, dog, and human liver microsomal P-450 enzymes was studied to obtain V max and K m values for Michaelis-Menten kinetics. The monkey had the highest V max value for the conversion of IFP to IFP-oxon (desulfuration), 162 nmol isofenphos hr −1 per 1.3 nanomoles P-450, followed by guinea pig (98), rat (66), dog (43), and human (14). The K m values for the desulfuration of isofenphos were 19.2, 7.4, 14.1, 23.3, and 18.4 μM, respectively, for the monkey, guinea pig, rat, dog, and human. The V max values for the dealkylation process (conversion of IFP to d- N-IFP) were 64.6, 17.2, 9.7, and 7.3 nmol isofenphos hr −1 per 1.3 nanomoles P-450 for the monkey, rat, dog, and human, respectively. For the dealkylation process, monkey had the highest K m value, 16.3 μM IFP, followed by human (11.2), rat (9.9), and dog (9.3). The rate of metabolism of IFP-oxon and d- N-IFP to d- N-IFP-oxon were separately studied. The V max and K m values obtained in this study for animal and human liver P-450 enzymes will be used to develop a PB-PK/PB-PD model to predict the fate and toxicity of isofenphos in animals and man.