Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal membranes.
Oral drugs can face stability issues during their shelf life or within the GI tract, leading to poor bioavailability. Two main issues are degradation into an inactive form and interactions with components in the dosage form or GI tract, which can result in poorly soluble or unabsorbable complexes. Enteric coating of orally administered drugs is a common strategy for protecting them from the stomach's acidic environment. For instance, erythromycin degrades quickly in an acidic stomach, but an enteric coating can stabilize it, enhancing bioavailability.
Approximately 60% of oral drugs are chiral (having two forms that are mirror images of each other, called enantiomers), with the majority marketed as racemic mixtures (with equal amounts of each enantiomer). Enantiomers often exhibit different physicochemical properties, such as melting points and solubilities, directly impacting dissolution rates. For example, one enantiomer may form a more stable crystalline structure, leading to slower dissolution, while the other might have a less stable form that dissolves more readily.
Despite identical physical and chemical properties, enantiomers have significant spatial configuration differences, leading to different interactions with biological targets. Passive biological processes rely solely on a molecule's physical and chemical characteristics and do not show selectivity for one isomer over another. However, biological processes requiring drug interaction with a macromolecule, such as protein binding, may exhibit stereoselectivity, as only one of the drug's enantiomers can bind to its carrier.
Since most drugs are absorbed passively, they do not display stereoselectivity. Conversely, evidence of stereoselective absorption indicates that a drug is absorbed through a carrier-mediated process. In drug development, optimizing permeability, ensuring stability, and understanding stereochemistry are critical for enhancing drug efficacy, safety, and bioavailability, ultimately determining a drug's therapeutic success.
