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 (∼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 AUCiv{mi,P}, AUCpo{mi,P}, and AUCpo{pmi} for both the TM and SFM, whereas a larger AUCiv{pmi} existed for the SFM. The AUC{pmi} was influenced by metabolite parameters only: binding, absorptive (ka{mi}) and luminal degradation (kg{mi}) constants, intrinsic clearances for metabolism (CLint,met,I{mi}), apical efflux (CLint,sec,I{mi}), and basolateral transfer (CLd1{mi} and CLd2{mi}) for the metabolite. By contrast, the AUC{mi,P} was influenced additionally by precursor parameters: rate constants ka and kg, and CLint,met,I and CLint,sec,I, but not the basolateral transfer clearances. The drug parameters: CLint,met,I and ka increased whereas CLint,sec,I decreased AUC{mi,P}, and the effect of secretion was counterbalanced by reabsorption with high ka 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.
Footnotes
-
This work was supported by the Canadian Institutes for Health Research [Grant MOP89850].
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.022483.
-
ABBREVIATIONS: AUC, area under the concentration-time curve; {mi,P}, metabolite formed from precursor; {pmi}, preformed metabolite; PBPK, physiologically based pharmacokinetic model; TM, traditional model; SFM, segregated flow model; QI, blood flow for the whole intestine; P, precursor; CLd1 and CLd2, basolateral, transfer intrinsic clearances between blood and tissue for the TM, or between blood and the enterocytes layer for the SFM; CLint,met,I, metabolic intrinsic clearance of precursor; CLint,sec,I, secretory intrinsic clearance of precursor at the apical membrane; ka, rate constant of absorption for precursor; kg, rate constant of luminal transit and degradation; Fabs, fraction of drug absorbed from the intestinal lumen into intestine tissue; Qen, blood flow for the enterocyte layer; Qs, blood flow for the serosal layer; CLd3 and CLd4, transfer intrinsic clearances between serosal blood and serosal tissue; {mi}, qualifier for metabolite (formed and preformed); F{pmi}, the bioavailability of the preformed metabolite.
- Received May 25, 2008.
- Accepted October 20, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|