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Evaluation of the Assumptions of an Ontogeny Model of Rat Hepatic Cytochrome P450 Activity

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada (F.A.E., J.A.); Department of Anatomy, Jordan University of Science and Technology, Irbid, Jordan (M.Z.A.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (P.J.M.)

We previously reported an ontogeny model of hepatic cytochrome P450 (P450) activity that predicts in vivo P450 elimination from in vitro intrinsic clearance. The purpose of this study was to conduct investigations into key assumptions of the P450 ontogeny model using the developing rat model system. We used two developmentally dissimilar enzymes, CYP2E1 and CYP1A2, and male rats (n = 4) at age groups representing critical developmental stages. Total body and liver weights and hepatic microsomal protein contents were measured. Following high-performance liquid chromatography analysis, apparent K_M and V_max estimates were calculated using nonlinear regression analysis for CYP2E1- and CYP1A2-mediated chlorzoxazone 6-hydroxylation and methoxyresorufin O-dealkylation, and V_max estimates for p-nitrophenol and phenacetin hydroxylations, respectively. Hepatic scaling factors and V_max values provided estimates for infant scaling factors (ISF). The data show microsomal protein contents increased with postnatal age and reached adult values after postnatal day (PD) 7. Apparent K_M values were similar at all developmental stages except at PD7. Developmental increases in probe substrate V_max values did not correlate with the biphasic increase in immunoquantifiable P450. The activity of two different probe substrates for each P450 covaried as a function of age. A plot of observed ISF values as a function of age reflected the developmental pattern of rat hepatic P450. In summation, these observations diverge from several of the model's assumptions. Further investigations are required to explain these inconsistencies and to investigate whether the developing rat may provide a predictive paradigm for pediatric risk assessment for P450-mediated elimination processes.

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