Received for publication May 27, 2008.
Revised October 19, 2008.
Accepted for publication October 20, 2008.

Disparity in intestine disposition between formed and preformed metabolites and implications: a theoretical study

Abstract

Metabolite in safety testing has been proposed for toxicity assessments. The question on how exposure of the synthetic metabolite compared to that of the formed metabolite was appraised kinetically using physiologically-based pharmacokinetic (PBPK) 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 so as to account for the higher extent of metabolism observed with oral vs. systemic dosing of drugs. Theoretical solutions for the areas under the curve of the formed metabolite after oral (po) and intravenous (iv) 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 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}). 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 secretion was counterbalanced by reabsorption with high k_as. The simulated time-courses and the AUC{pmi} and AUC{mi,P} resulting from iv and po routes of administration of preformed metabolite and precursor differed, inferring that the kinetics of the preformed and formed metabolites is not identical.

Key words: drug toxicity, drug transport, metabolite kinetics, pharmacokinetic/pharmacodynamic modeling, pharmacokinetic modeling, physiologically-based modeling, physiologically-based pharmacokinetics, toxicity testing, toxicokinetics