Contribution of Intestinal Cytochrome P450-Mediated Metabolism to Drug-Drug Inhibition and Induction Interactions

Abstract

Current drug-drug interaction (DDI) prediction models incorporate intestinal interaction as the ratio of the intestinal availability in the presence and absence of an inhibitor/inducer (F(G)' and F(G), respectively). The incorporation of the gut is commonly associated with a reduced number of false negative predictions; however, in some instances a trend for over-prediction is apparent. This differential success is highly dependent on the initial model assumptions and parameter estimates used (often inconsistent between the datasets) and cannot be associated exclusively with the incorporation of the intestine. The current review provides an assessment of the contribution of intestinal inhibition and induction in conjunction with different perpetrator and victim drug-related properties, focusing in particular on victim drugs with high intestinal first-pass extraction (>75%). Recommendations are given in order to avoid significant over-estimation of true positives and increased number of false positive predictions. This review discusses advantages and limitations of different in vitro and in vivo methods for assessing intestinal availability and associated inter-individual variability, due to the sensitivity of the DDI prediction models to the F(G).

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

“…Recently, a number of in vitro systems have been used to predict the magnitude of rifampin induction in vivo (Fahmi et al, 2008b;Shou et al, 2008;Galetin et al, 2010). Whereas hepatocytes are considered the "gold standard," both HepaRG and Fa2N-4 have been proposed as appropriate surrogates for assessment of CYP3A4 induction (Fahmi et al, 2008a;Hariparsad et al, 2008;McGinnity et al, 2009).…”

“…Initially, quantitative predictions from in vitro data were based on calculation of an induction score or induction ratio (Kato et al, 2005;Ripp et al, 2006). More recently, prediction models incorporating either solely induction or induction in combination with inhibition mechanisms have been applied (Fahmi et al, 2008b;Shou et al, 2008;Galetin et al, 2010;Kirby et al, 2011). These prediction models use a static average or maximal inducer plasma concentration assumed to reflect steady-state enzyme activity before substrate administration.…”

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

“…These three intestinal models are viewed as competent to describe the immediate removal of the formed metabolite by excretion or sequential metabolism within the intestine and/or further processing by liver, for drugs and metabolites exhibiting varying permeability properties (Cong et al, 2000;Yang et al, 2006Yang et al, , 2007Gertz et al, 2010;Sun and Pang, 2010). The models are more prepared to supply mechanistic insight into the pharmacokinetics of drugs and their metabolites and allow inclusion of transporters into different organ components (apical or basolateral membranes) to discriminate between the permeability properties of the drug and its formed metabolite in permitting or delimiting influx and efflux in drug and metabolite processing (Pang et al, 2008;Darwich et al, 2010;Galetin et al, 2010;Gertz et al, 2010;Rowland Yeo et al, 2010;Chow and Pang, 2013). By virtue of inclusion of transport and eliminatory events, these physiologically based models are able to more accurately describe the net appearance of the formed metabolite into the systemic circulation, because metabolite levels can be drastically reduced as a result of sequential metabolism (Pang and Gillette, 1979).…”

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

“…This is due to the relatively high enterocytic drug concentration and the considerably lower blood flow to the intestine in comparison to the liver that allows prolonged exposure to the intestinal metabolizing enzymes. The contribution of intestinal first-pass metabolism has been shown indirectly for a number of CYP3A drugs administered both intravenously and orally in the absence and presence of inhibitors/inducers (Galetin et al, 2010). Such studies have allowed delineation of the relative roles of the liver and intestine and are particularly abundant for midazolam and to a lesser extent for cyclosporine, tacrolimus, alfentanil, and nifedipine.…”