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Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Metabolite in safety testing has been proposed for toxicity assessments. The question of how exposure of the synthetic metabolite compared with that of the formed metabolite was appraised kinetically by using physiologically based pharmacokinetic models, the (traditional) physiological model (TM), and segregated flow (SFM) models. The SFM differs from the TM and describes a partial (10% total) intestinal flow that perfuses the absorptive, metabolic, and secretory enterocyte layer to account for the higher extent of metabolism observed with oral versus systemic dosing of drugs. Theoretical solutions for the areas under the curve (AUC) of the formed metabolite after oral and intravenous administration of the precursor (AUC{mi,P}) and preformed, synthetic metabolite (AUC{pmi}) showed identical AUC_iv{mi,P}, AUC_po{mi,P}, and AUC_po{pmi} for both the TM and SFM, whereas a larger AUC_iv{pmi} existed for the SFM. The AUC{pmi} was influenced by metabolite parameters only: binding, absorptive (k_a{mi}) and luminal degradation (k_g{mi}) constants, intrinsic clearances for metabolism (CL_int,met,I{mi}), apical efflux (CL_int,sec,I{mi}), and basolateral transfer (CL_d1{mi} and CL_d2{mi}) for the metabolite. By contrast, the AUC{mi,P} was influenced additionally by precursor parameters: rate constants k_a and k_g, and CL_int,met,I and CL_int,sec,I, but not the basolateral transfer clearances. The drug parameters: CL_int,met,I and k_a increased whereas CL_int,sec,I decreased AUC{mi,P}, and the effect of secretion was counterbalanced by reabsorption with high k_a values. The simulated time courses for the metabolites and the AUC{pmi} and AUC{mi,P} resulting from intravenous and oral routes of administration of preformed metabolite and precursor differed, inferring that the kinetics of the preformed and formed metabolites are not identical.