Send Orders of Reprints at [email protected] 776 Current Topics in Medicinal Chemistry, 2013, 13, 776-802 Intestinal Targeting of Drugs: Rational Design Approaches and Challenges Kevin J. Filipski1,*, Manthena V. Varma2, Ayman F. El-Kattan2, Catherine M. Ambler3, Roger B. Ruggeri1, Theunis C. Goosen2 and Kimberly O. Cameron1 1Cardiovascular, Metabolic, and Endocrine Diseases Chemistry, Pfizer Worldwide Research and Development, Cam- bridge, MA, USA; 2Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, Groton, CT, USA; 3Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Groton, CT, USA Abstract: Targeting drugs to the gastrointestinal tract has been and continues to be an active area of research. Gut- targeting is an effective means of increasing the local concentration of active substance at the desired site of action while minimizing concentrations elsewhere in the body that could lead to unwanted side-effects. Several approaches to intestinal targeting exist. Physicochemical property manipulation can drive molecules to large, polar, low absorption space or alter- natively to lipophilic, high clearance space in order to minimize systemic exposure. Design of compounds that are sub- strates for transporters within the gastrointestinal tract, either uptake or efflux, or at the hepato-biliary interface, may help to increase intestinal concentration. Prodrug strategies have been shown to be effective particularly for colon targeting, and several different technology formulation approaches are currently being researched. This review provides examples of various approaches to intestinal targeting, and discusses challenges and areas in need of future scientific advances. Keywords: Drug, Gut, Intestine, Non-systemic, Prodrug, Soft drug, Targeting, Transporter. 1. INTRODUCTION significant distribution into the body. Central Nervous Sys- Tissue targeting has become an increasingly important tem (CNS) agents have not been traditionally considered area of research in drug discovery. Tissue targeting refers to tissue targeted since the highest measured brain to plasma having an increased local concentration of drug in a particu- ratios are most often 2 [13]; however, this is currently an lar tissue or region of the body that is the site of action for active area of research [14-15]. Kidney targeting strategies, that therapeutic target. It is usually done for safety purposes reviewed previously [16-17], have made use of amino acid- – i.e. the concentration of drug needed at the site of the de- linked prodrugs (e.g. N-acetyl--glutamyl sulfamethoxazole) sired therapeutic target for efficacy would lead to some un- that are cleaved by kidney-specific enzymes that recognize desired effect in another area of the body. This undesired this motif [18], lysozyme-tethered small molecules, polym- effect can be from off-target activity in another tissue, such eric carriers, and liposomes conjugated to antibodies. Among as the well-documented hERG liability of several drugs that oral drugs, liver targeting appears to be among the most sci- occurs from interaction of the drug substance with a potas- entifically advanced. Steraroyl-CoA desaturase (SCD) in- sium ion channel in the heart [1-4], or can result from on- hibitors [19-22], glucokinase activators [23], and next gen- target activity in an undesired tissue. For instance, a common eration HMG-CoA reductase inhibitors [5, 24] are recent side effect of statin therapy for hypercholesterolemia is my- examples of liver-targeted strategies whereby organic ion algia, and a less common but more serious adverse event is transporting polypeptides (OATPs), highly expressed in the rhabdomyolysis. These are thought to occur from statin inhi- liver, actively transport the small molecules of interest into bition of HMG-CoA reductase in the muscle, the same target the liver. This is complemented by low passive permeability that, when inhibited in the liver, leads to the desired effect of to restrict both passive exit out of the hepatocyte and diffu- sion into systemic tissues, thereby increasing the relative lipid lowering [5]. In either case, by targeting the specific concentration of the active drug in the liver versus undesired tissue of desired therapeutic action, the concentration of drug peripheral tissue (e.g. skin and eye for SCD inhibitors, pan- at the site of undesired action can be minimized, resulting in creas for glucokinase activators, and muscle for HMG-CoA an increased therapeutic index. reductase inhibitors). The concept of tissue targeting has long been embraced Modulation of targets within the gastrointestinal (GI) for certain tissues and therapeutic areas. Skin [6-7], eye [8], tract can impact a number of different therapeutic areas in- ear [9], and lung [10-12] therapies often increase the local cluding obesity, diabetes, infectious diseases, and inflamma- concentration of drug using targeted delivery methods (e.g. tory disorders, such as ulcerative colitis and Crohn’s disease. topical administration, inhalers), usually combined with Recent results from type 2 diabetic patients that have under- physicochemical properties of the molecule to prevent gone gastric bypass surgery suggest that a significant number of diabetics go into remission within days after surgery [25- *Address correspondence to this author at the Pfizer Worldwide Research and Development, 620 Memorial Dr, Cambridge, MA 02139, USA; 26]. Also, emerging data supports the importance of the gut Tel: +1 617 551-3267; Fax: +1 617 551-3082; microbiome on health and disease [27-31]. These recent de- E-mail: [email protected] velopments suggest the potential for an increased emergence 1873-5294/13 $58.00+.00 © 2013 Bentham Science Publishers Intestinal Targeting of Drugs Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 7 777 of disease-modifying targets within the GI tract. It is there- pends on the location of both the intestinal target and anti- fore important to ensure that rational design approaches to tissue, the nature of the chemical substrate, and desired pharmaceutically active compounds are available in order to pharmacokinetics and dynamics. An introduction to absorp- safely modulate these targets. As with other tissue-targeting tion and metabolism of orally dosed drugs will first be sum- approaches, increasing the intestinal concentration of drug marized to provide context for the various intestinal- versus anti-tissue should increase the safety margin [32-33]. targeting approaches. Gut-targeted inorganic or polymeric The degree of gut specificity required is highly target de- drugs, such as lanthanum carbonate [34-36], calcium acetate, pendent and ranges from requiring no systemic absorption sevelamer hydrochloride, sevelamer carbonate [34, 37], and (specific) to having some degree of uptake into the GI tract calcium polycarbophil [38-39] are beyond the scope of this (selective). In addition, intestinal targets can be luminal – review. within the intestinal lumen or on the luminal side of the api- cal membrane of the epithelium – and therefore no absorp- 2. GUT PHYSIOLOGY AND DRUG PHARMACOKI- tion is needed; or intracellular – within the enterocyte – or in NETICS the intestinal tissue on the basolateral side of the enterocyte, In humans, the gastrointestinal tract consists mainly of in which case some transport across the apical gut wall is the stomach, small intestine (duodenum, jejunum, and il- necessary. An intestinal-targeted drug can also be thought of eum), and large intestine (cecum, colon, and rectum). The as a non-systemic drug, that is, an oral drug with limited human GI tract is ~8.4 m long and the relative size of the systemic bioavailability. small intestine to the total length of the GI tract is 81% in This review will provide design approaches for selec- humans. The small intestine has a large surface area (200 m2) tively targeting the gut with an oral drug based on known that is provided by three anatomical modifications. The folds drugs and discovery programs, as well as potential strategies of Kerckring are grossly observable folds of mucosa that for future efforts. Approaches include the rational design of increase the surface area by 3-fold [40]. From the plicae cir- active compounds or prodrugs that have specific physico- cularis project microscopic finger-like pieces of tissue called chemical properties for limited absorption or high clearance, villi that increase the surface area by 10-fold for humans. identification of substrates for transporters within the gastro- Each villus is covered in microvilli, which increase the sur- intestinal tract or hepato-biliary interface, and the use of face area by 20-fold (Fig. (1)). As a result, the small intestine formulation technologies. The specific strategy chosen de- is considered the main site of absorption for nutrients and Fig. (1). Anatomy of intestinal tissue. (a) Intestinal section showing folds of Kerckring. (b) Structure of villus. (c) Enterocyte. MARIEB, ELAINE N., HUMAN ANATOMY & PHYSIOLOGY, 6th,©2004. Printed and Electronically reproduced by permission of Pearson Education, Inc., Upper Saddle River, New Jersey [42]. 778 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 7 Filipski et al. xenobiotics. There are several layers of tissue that comprise The transcellular pathway is the major route of absorp- the intestines and display discrete functions. Enterocytes, a tion for most drug molecules. In general, the rate of passive subtype of epithelial cells, are