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

Abstract

ABSTRACT: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 (ϳ10% 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.Metabolite-in-safety testing and the attainment of safe and efficacious drug use are key concerns in the drug development/surveillance paradigm. There has been a resurgence of interest in the testing of metabolites that are mediators of drug activity and toxicity due to the improvement in analytical methods for their detection, isolation, and characterization (Baillie et al., 2002). Metabolite testing is recommended, especially when metabolites are unique and identified only in humans, or when the metabolite exists at disproportionately higher levels in humans (Ͼ10%) than the animal species that was used for standard, nonclinical toxicology testing (Naito et al., 2007) (February, 2008 FDA Guidance for Industry, Safety Testing of Drug Metabolites. Pharmacology and Toxicology; http://www.fda.gov/cder/guidance/). It has been proposed that a metabolite is considered to be a major metabolite when the metabolite represents Ͼ10% (Davis-Bruno and Atrakchi, 2006) or 25% exposure (or area under the curve) of the precursor (Baillie et al., 2002). Others have suggested the estimate to be based on unbound concentration in the circulation or amounts in the excreta (Smith and Obach...

Physiological Modeling to Understand the Impact of Enzymes and Transporters on Drug and Metabolite Data and Bioavailability Estimates

“…The original models are somewhat restrictive, since the drug forms only one metabolite, and the formed metabolite is further metabolized. The areas under the curve of the formed metabolite (AUC{mi,P}) from po dosing for TM and SFM are the same, whereas that from iv dosing differs in the flow term, Q I or Q PV for TM and Q en (enterocyte flow, or a small portion of Q I ) for SFM (37).…”

“…One is the traditional model (TM) and the second is the segregated flow model (SFM) (37). The latter is more appropriate, since many compounds are observed to exhibit a greater extent of metabolism with the oral (po) route vs. the intravenous (iv) route, or route-dependent intestinal metabolism (38).…”

“…PBPK models involving the intestine that consider transporters and enzymes have been used previously to describe intestinal metabolism (37). One is the traditional model (TM) and the second is the segregated flow model (SFM) (37).…”

Pharmacokinetic Interplay of Phase II Metabolism and Transport: A Theoretical Study

“…A traditional PBPK model of the small intestine 6,25,29,30 was used to examine the transport-metabolism interplay, with minor modifications (Fig. 3).…”

Understanding the pharmacokinetics of prodrug and metabolite

“…[5][6][7][8][9][10] A thorough understanding of prodrug kinetics is daunting and may be achieved using sophisticated physiologically based pharmacokinetic (PBPK) modeling. [11,12] To get some insight pertinent to prodrug kinetics, we consider a simple scheme for the fate of a prodrug (P) after intravenous administration (Fig. 1).…”