oa Editorial [Hot topic: Role of Intestinal Transporters and Metabolism in the Oral Absorption of Drugs and Prodrugs (Guest Editor: Manthena V. Varma)]

Oral bioavailability is a function of intestinal absorption and first-pass metabolism. Future chemistry space is predicted to be relatively hydrophilic; where the development issues associated with toxicity are expected to be low [1]. This may result in limited passive membrane permeability and increased reliance on membrane transporters for intestinal absorption. A growing list of membrane transporters has been recognized in almost all tissues, although a few of them are well-characterized and appreciated to be determinants of drug disposition. Enterocytes express several transporters, belonging to the adenosine triphosphate binding cassette (ABC) and the solute carrier (SLC) superfamilies, on the apical and basolateral membranes for the influx or efflux of endogenous and drug substances.Several successful chemistries have been reported to target some of the vital intestinal uptake transporters or avoid efflux pumps to enhance the absorption. In the light of this, the contribution by Varma et al. reviews the molecular and functional characteristics along with the structure-activity relationships of the vital intestinal transporters. This chapter also provides several case examples on targeting uptake transporters and circumventing efflux pumps via chemistry and prodrug approaches that would be helpful to the discovery teams working in this direction. Although the small intestine is regarded as an absorptive organ and may act as a rate-limiting barrier, it also has ability to metabolize drugs by several pathways involving both phase I and phase II reactions and may lead to limited systemic exposure. CYP3A4, the most abundant P450 present in human hepatocytes and intestinal enterocytes is implicated in the metabolic elimination of many drugs [2, 3]. The next common metabolic elimination pathways are due to glucuronidation and ester hydrolysis. It has also been proposed that drug interactions involving CYP3A inhibition and induction may be largely occurring at the level of the intestine [4, 5]. In a recent analysis of 309 drugs with intravenous and oral clinical pharmacokinetic data, we noted that roughly 30% of the drugs in the data set show more than 20% intestinal extraction, underscoring the importance of considering intestinal metabolism in predicting bioavailability and dose projections in drug discovery and development settings [6]. Although, the average human intestinal content of CYP3A has been estimated to be only about 1% of the average hepatic content [2], the data set indicated that intestinal metabolism may contribute to first-pass extraction more than the hepatic metabolism for certain drugs. This could be a result of better access to the enzymes in the enterocytes; a function of transcellular flux and the large absorptive area, and/or due to reduced access to hepatic enzymes because of potential plasma protein binding [7]. The intestinal first-pass metabolism in humans is indirectly estimated under certain assumption, by comparing the plasma AUCs following intravenous and oral dosing. Early studies in liver transplant patients during the anhepatic phase indicated the relative importance of the gut extraction to the first-pass metabolism for drugs such as midazolam and cyclosporine [8]. Further clinical evidences were obtained in the grape-fruit juice interaction studies, where coadministration of grape-fruit juice result in the inhibition of gut CYP3A4 without significantly affecting the hepatic metabolism of drugs like felodipine [9]. However, assessment of the quantitative contribution of intestinal and hepatic extraction in first-pass metabolism is limited by ethical and technical challenges. There exist gaps in predicting the gut extraction before the clinical development stage due to shortcomings in the in vitro-in vivo extrapolation (Eg. utilizing human intestinal microsomal stability). Also species differences exist where rat and monkey typically under-predicts the fraction escaping gut extraction (Fg) in human [10, 11]. Recently, transgenic mice model with constitutive expression of human CYP3A4 in liver or intestine that provides quantitative estimation of the contribution of hepatic and gut extraction to the first-pass metabolism has been generated [5]. Overall, due to limited access to the sophisticated models and complexities with in vitroin vivo extrapolation and species differences, intestinal metabolic disposition is far from consistently predictable. Recent studies demonstrated that efflux transporters present on the apical membrane of enterocytes, in particular P-glycoprotein, can affect the intestinal metabolism by prolonging the enterocytic transit time and consequent exposure to CYP3A enzymes [12]. A significant overlap has also been identified between substrates and inhibitors of CYP3A4 and Pglycoprotein, suggesting that these two proteins may act complementarily in further limiting Fg of CYP3A substrates. Due to the complexity in these biochemical processes and the lack of availability of extensive experimental models, application of physiologically-based pharmacokinetic (PBPK) models and systems biology seem to provide quantitative prediction of first-pass metabolism. The chapters by Darwich et al. and Fan et al. describe the mechanistic models and explore new PBPK models to achieve improved predictions. These emerging tools aim towards appropriate reconstruction of the physicochemical, anatomical and biochemical complexities in mathematical terms. Utilizing experimental data majorly derived from in vitro tools, Darwich et al. recognized the combination of parameter (passive permeability, P-glycoprotein efflux kinetic and enzyme kinetic) values where the gut extraction would be expected to be high. Fan et al. evaluated the intestinal and liver PBPK models to predict the contributions of enzymes and transporters on intestinal and hepatic availability, and studied the impact of the model variables on oral bioavailability. With the involvement of saturable processes in the transport and metabolism, the prediction of non-linear pharmacokinetics and drug-drug interactions (DDIs) is likely to play a large role in preclinical and clinical development. The contribution from Tachibana et al. reviews the semi-quantitative and quantitative methods for predicting intestinal DDIs caused by inhibition of CYP3A4 and P-glycoprotein. They point to the importance of accuracy in the in vitro enzyme and transporter kinetics parameters to achieve reliable predictions. While the discussion in the above three articles majorly focus on the CYP3A and P-glycoprotein, these models can be conceptually applied to the rest of the transporters and enzymes. Won et al. discuss the effect of dietary substances on the drug disposition, which is often overlooked. While reviewing the advances in the understanding of mechanisms involved in the drug-dietary substances interactions, authors argued on the need to further characterize the specific dietary components that alter drug disposition, in the process of predicting such interactions. It is also apparent that systemic availability of ester drugs and prodrugs may be hindered by the hydrolytic enzymes present in the enterocytes. Understanding the esterase activity is therefore valuable with drug industry diverting significant resources to prodrugs discovery and development. Imai and Ohura discussed the characteristics of human intestinal carboxylesterase and its role in the absorption of prodrugs and drug candidates with ester functionalities. Authors also discussed the pros and cons of available tools for predicting the gut extraction of prodrugs. Collectively, the articles of this Current Drug metabolism issue provide comprehensive and updated information on several vital areas of intestinal drug disposition and points to the current challenges and scientific gaps. As guest editor, I owe great thanks to each one of the authors for the excellent contributions. I also owe a special thanks to the reviewers for providing valuable inputs.