Oral drug absorption rate-limiting

Bergstrom CAS (2005) In silico predictions of drug solubility and permeability two rate-limiting barriers to oral drug absorption. Basic Clin Pharmacol Toxicol 96 156-161. 

RATE-LIMITING STEPS IN ORAL DRUG ABSORPTION... 

Usually, an increase in Cg that would affect the dissolution rate would occur only when another process, such as membrane transport or stomach emptying, becomes the rate-limiting step in drug absorption. As a general rule pharmacists should advise patients to take their oral medications with a full glass of water to ensure that dissolution occurs under optimal conditions. 

Orally administered dosage forms are absorbed into the systemic circulation following dissolution in the GI tract. Because substances must be in solution for the absorption from the GI lumen, the absorption rate of poorly water-soluble drugs is limited by their rate of dissolution. The dissolution rate is affected by the unique physicochemical properties of the drug and by physiological factors the pH, composition, and hydrodynamics of the GI medium. 

Dissolution indicates the rate-limiting step for compound absorption when drugs are administered orally. The solubility of a pharmaceutical compound represents its maximum concentration in an aqueous buffer. Additional compound will not dissolve above this concentration. The solubility value is often heavily dependent upon pH and temperature and is typically measured at physiologically important pH levels and body temperature. The standards for dissolution testing are determined by the United States Pharmacopoeia (USP). Testing typically requires sampling of a solution at 15, 30, 45, and 60 min for immediate-release products. /./Pl.C is ideally suited for use in conjunction with USP apparatus types I or II and can rapidly analyze multiple time points or replicate samples. 

Transport of the benzodiazepines into the brain is rapid, the rate of uptake being determined by the physicochemical properties of the drug. Absorption from the gastrointestinal tract, or from an injection site, is the rate-limiting step governing the speed of onset of the therapeutic response. Oral absorption is more rapid when the drug is taken on an empty stomach. 

To meet the need of conducting HTS for ADME-Tox properties, many slow and expensive in vivo ADME assays are now being replaced by in vitro cell models. For intestinal absorption, Caco-2 cell lines and Madin Darby canine kidney (MDCK) cell lines are widely used to predict the absorption rate of candidate drug compounds across the intestinal epithelial cell barrier. A number of models for Caco-2 cell permeability and MDCK cell permeability have been reported that predict the oral absorption properties of drugs, mostly limited to small organic molecules. Caco-2 and MDCK permeability are related to "A" and "D" in the ADME-Tox. 

---