In addition we aim to shed light into the long-standing discussion through a quantitative assessment of this impact, implementing the models in a middle-out approach to simulate pharmacokinetic outcomes for three drug groups defined according to disposition characteristics.ĭiscerning between cycling/circulation and reabsorptionĮnteric reabsorption occurs when a fraction of drug transferred from the arterial bloodstream to the gastrointestinal tract (GIT) is subsequently reabsorbed back into the systemic circulation. In this work, by using semi-mechanistic pharmacokinetic models, we analyze and discuss the impact of different mechanisms leading to enteric reabsorption on drug clearance, volume of distribution and bioavailability. Although other authors have further argued with different methodologies that enterohepatic reabsorption increases AUC by decreasing systemic clearance 8, 9 and/or increasing oral bioavailability 8, 10, the current understanding of its pharmacokinetic impact remains unclear. 6, 7, used the same and more complex models to deduce that drug clearance and oral bioavailability were independent of enterohepatic reabsorption and thus the AUC ratio was an unbiased estimator of the oral bioavailability. Applying this model to cimetidine observations, authors suggested that the area under the plasma concentration–time curve (AUC) was dependent on the extent of reabsorbed drug, and since this process was dependent on the administration route the ratio between oral and intravenous AUC would not be a suitable measure of oral bioavailability. The liver was included as part of the central compartment and therefore, the first-pass effect was not mechanistically accounted for. The proposed model included a two-compartmental drug distribution structure plus a compartment accounting for the gallbladder, from where the drug was secreted into the gut in a discontinuous process. In 1980, Veng-Pedersen and Miller developed a model to describe cimetidine plasma concentrations after single oral and intravenous doses 5. On the other hand, it seems settled that both volume of distribution and drug half-life are increased with higher reabsorption.ĭiscussion about the impact of reabsorption in drug clearance and oral bioavailability has been around for a long time. Interestingly, within these articles, the impact of drug reabsorption on fundamental pharmacokinetic parameters such as the systemic clearance and the oral bioavailability is undefined. Several extensive reviews with focus on enterohepatic reabsorption mechanistic aspects, modeling approaches and pharmacokinetic consequences have been published 1– 4. Findings provide background to explain and forecast the role that this process can play in pharmacokinetic variability, including drug-drug interactions and disease states.ĭrug reabsorption has always been a pharmacokinetic challenge, both in modeling blood/plasma multiple-peak drug profiles and in interpreting its impact on drug elimination clearance and bioavailability. Conversely, EGR had negligible impact in all pharmacokinetic parameters. Results show that an increase in EHR can significantly reduce the clearance of drugs A and B, increase bioavailability of B drugs, and increase the volume of distribution for all drugs. A simulation-based analysis was carried out considering three drug types with the potential for reabsorption, classified according to their primary route of elimination and their hepatic extraction: (A) hepatic metabolism-low extraction (B) hepatic metabolism-intermediate/high extraction (C) renal excretion. In this work, we propose semi-mechanistic pharmacokinetic models to reflect EHR and EGR and compare their respective impact on primary pharmacokinetic parameters. In addition, the impact of drug reabsorption on systemic clearance, volume of distribution and bioavailability has been a subject of long-standing discussions. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR). This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation.
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