Editorial [Hot Topic: Intestinal First-Pass Metabolism - Bridging the Gap Between In Vitro and In Vivo (Prediction of Intestinal First-Pass Metabolism (Guest Editor: Aleksandra Galetin))]

The ability to successfully predict pharmacokinetic properties plays a crucial role in the selection of candidate drugs and significantly reduces the number of potential failures in drug development. Current drug candidates typically show a very high affinity for the target receptors; however, the drawback is that many new lead compounds represent large, lipophilic molecules with low solubility, dissolution and/or permeability and consequently show poor absorption properties. In vitro-in vivo prediction and application of in silico methods for clearance and drug-drug interaction prediction from hepatic cytochrome P450 data have been widely accepted by both pharmaceutical companies and academia, and meet certain regulatory requirements [1]. However, the application of these approaches to extrahepatic tissues, including the intestine, has proved challenging and less definitive. Estimates of intestinal clearance are not routinely incorporated into in vitro-in vivo strategies and this may partially explain the clearance under-prediction trend often observed [2].

The aim of this special issue of Current Drug Metabolism is to provide a broad perspective, both from academia and industry, on intestinal absorption and the impact of intestinal first-pass metabolism on both clearance and drug-drug interaction prediction. The issue also considers our in silico abilities to bridge the gap between the increasing amount of intestinal in vitro data and the importance of intestinal first-pass metabolism in vivo. Overviews of the biopharmaceutical and pharmacokinetic variables and their impact on the prediction of the drug absorption from either chemical structure and/or in vitro data is presented, focusing in particular on the estimation and application of intestinal permeability [3,4]. The role of uptake and efflux transporters and their interplay with the metabolic enzymes is becoming an increasingly important issue for drug candidates. Recently, drug elimination mechanisms (e.g., via metabolism, or coupled with uptake/efflux transporters or renal clearance) have been suggested as criteria to extend the Biopharmaceutical Classification System beyond the use of drug permeability/solubility characteristics to the prediction of drug disposition [5]. The limitations of the cellular systems and potential overestimation of the significance of efflux transporters on the intestinal absorption are also discussed [3].

ROLE OF THE INTESTINE IN THE CLEARANCE PREDICTION Over recent years a number of studies have assessed the catalytic activity of intestinal metabolic enzymes in comparison to the liver, focusing predominantly on CYP3A4/CYP3A5 as well as a range of glucuronidating (UGT) enzymes. Although intuitively one would expect the activity of enzymes in both organs to be comparable, a number of in vitro studies have reported differential importance of the intestine relative to the liver. In addition, inter-individual variability in P450/UGT expression in both liver and intestine and their relative abundance in the corresponding organs have generally not being taken into account. A recent study by Galetin and Houston [6] has shown comparable intestinal and hepatic catalytic activity (when expressed per pmol of P450 enzyme) of the major P450 enzymes. Therefore, it would be reasonable to expect that once normalized for the relative abundance of the enzyme investigated, hepatic or recombinant data would be equally useful for the prediction of intestinal clearance once an appropriate mechanistic model is applied. Although this approach is applicable for P450 enzymes [4], certain specific issues need to be addressed in case of phase II enzymes. For example, the relative UGT expression levels in vivo are not clearly defined. A recent study by Cao et al. [7] indicated a 3-fold higher expression of UGTs relative to CYP3A4 in human duodenum. However, as the expression of intestinal metabolic enzymes, and transporters, follows certain gradient patterns along the intestine and within the villi, this will not necessarily reflect the UGT:P450 abundance ratio along the whole length of the gut. In addition, the identification of appropriate extrahepatic scaling factors represents a major challenge. Only recently, has a consensus on such numbers been reached for the scaling of hepatic data [8], and there is no such comprehensive data available for the analysis of the intestinal microsomal recovery......