Author DAVID DAHLGREN
Before an orally administered drug reaches the systemic circulation, it has to dissolve in the intestinal fluids, permeate across the intestinal epithelial cell barrier, and pass through the liver, the permeation rate of drug compounds can be low and show regional differences, regional intestinal permeability values of model compounds in human, effects of absorption-modifying pharmaceutical excipients (AMEs) on the intestinal permeability of the model compounds, intestinal permeability, absorption-modifying excipients, nature of the gastrointestinal (GI) tract is to prevent absorption and translocation of potentially harmful luminal constituents into the central circulation, while still allowing the absorption of nutrients and water, obstacles associated with the oral administration route that need to be overcome for successful systemic drug treatment, drug product/formulation (e.g., capsule, tablet) must initially disintegrate, so that drug particles can dissolve in the GI fluid , The drug solubility in the intestinal GI fluids must be high enough to enable a sufficiently fast dissolution rate. The free drug molecules in solution also determine the concentration gradient between the intestinal lumen (i.e., the inside of the intestinal tube) and the blood; this gradient is the driving force for permeability and absorption, where permeability is the transport across the apical membrane, the rate limiting membrane barrier. A reduction in the luminal free drug concentration can occur if the drug molecule precipitates, is chemically or enzymatically degraded, or forms complexes with the luminal content. The drug molecules are considered absorbed after they have been transported across the outer lipophilic cell membrane, and this membrane can impose substantial resistance to large and/or hydrophilic drug molecules. Finally, before an absorbed drug molecule is introduced into the central blood circulation, it passes through the intestinal barrier and liver, where it may be metabolized and lose its pharmacological effect, or be excreted with bile back into the intestines , drug discovery process, candidate drug molecules are selected based on physicochemical properties, the affinity for the pharmacological target, membrane transport properties, chemical and metabolic stability, and their safety/toxicity profile, high cost is also associated with the high attrition rate in drug development, the high cost and attrition rate at the later stage of the drug-development process, 16% of all drug compounds that fail in the early phase of clinical development do so because of undesirable pharmacokinetic properties, development of formulations containing drugs with low intestinal solubility and/or low intestinal permeability, drug product can be designed to mitigate the impact of unfavorable PK properties, mass transfer of luminally dissolved drug molecules across the apical intestinal epithelial cell barrier includes one, or several, of the following transport mechanisms: passive lipoidal and paracellular diffusion, and/or carrier-mediated transport in both the absorptive and secretive (efflux) directions, Carrier-mediated (CM) transport is the process whereby a compound is transported into (influx) or out of (efflux) the intestinal epithelial cell cytosol across the lipoidal membrane bilayer using a protein transporter. CM transport can be either active or facilitated, Active transport uses energy to create a concentration gradient across membranes, and is classified as primary or secondary, CM transport is important for absorption of water soluble nutrients, such as glucose, vitamins, and amino acids, but this transport mechanism can also be important for drug compounds, dissolved drug molecule must diffuse across a water layer with limited convection covering the epithelial cell membrane before it can be absorbed
