Absorption rate-limiting step

The rate-limiting step in the absorption of those compounds that readily penetrate the intestinal membrane (i.e., have a large permeability coefficient) may be the rate at which blood perfuses the intestine. However, absorption will be independent of blood flow for those compounds that are poorly permeable. Extensive studies have illustrated this concept in rats [106,107]. The absorption rate of tritiated water, which is rapidly absorbed from the intestine, is dependent on intestinal blood flow, but a poorly absorbed compound, such as ribitol, penetrates the intestine at a rate independent of blood flow. In between these two extremes are a variety of intermediate compounds whose absorption rate is dependent on blood flow at low flow rates but independent of blood flow at higher flow rates. By altering blood flow to the intestine of the dog, as blood flow decreased the rate of sulfaethidole absorption also decreased [108]. These relationships are illustrated in Fig. 16. 

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. 

Fig. 7.5. The Biopharmaceutics Classification System (BCS) provides a scientific basis for predicting intestinal drug absorption and for identifying the rate-limiting step based on primary biopharmaceutical properties such as solubility and effective intestinal permeability (Pefr). BCS serves as a product control instrument. The BCS divides drugs into four different classes based on their solubility and...

Reduction of particle size increases the total specific surface area exposed to the solvent, allowing a greater number of particles to dissolve more rapidly. Furthermore, smaller particles have a small diffusion boundary layer, allowing faster transport of dissolved material from the particle surface [58]. These effects become extremely important when dealing with poorly water-soluble drugs, where dissolution is the rate-limiting step in absorption. There are numerous examples where reduction of particle size in such drugs leads to a faster dissolution rate [59-61], In some cases, these in vitro results have been shown to correlate with improved absorption in vivo [62-64]. 

Since the rate of absorption of many drugs from the gastrointestinal tract is controlled by their dissolution rate, this becomes the rate-limiting step. Accurate and reliable measurements of dissolution rate are therefore required in the pharmaceutical sciences. The measurement and interpretation of the dissolution rates of solid drugs in the pure state or from formulations, such as tablets, capsules, and suppositories, has an extensive pharmaceutical literature [95-100]. Moreover, the design, operation, and interpretation of dissolution rate measurements on pharmaceutical solids have been the subject of considerable scientific study, technical development, and debate. 

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. 

Facilitated Diffusion. Temporary combination of the chemical with some form of carrier occurs in the gut wall, facilitating the transfer of the toxicant across the membranes. This process is also dependent on the concentration gradient across the membrane, and there is no energy utilization in making the translocation. In some intoxications, the carrier may become saturated, making this the rate-limiting step in the absorption process. 

Table 2 Rate-Limiting Step to Absorption and Requirements for Dissolution According to BCS Classification of the Drug Substance...

A higher degree of correlation may be expected with MR formulations, since release from the dosage form is purposely intended to be the rate-limiting step to absorption in these formulations. 

Since transport across the syncytiotrophoblast layer is the rate-limiting step in the absorption of substances from the maternal circulation to the fetal, these cells can provide information on uptake processes which are subject to intracellular regulatory mechanisms or affected by intracellular metabolism. However, it is very difficult to isolate this layer because of its syncytial nature. As a result, the undifferentiated precursor cytotrophoblast cells have been isolated and cultured. These cells do not proliferate in culture, but aggregate and spontaneously differentiate into syncytiotrophoblasts [49],... 

Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, Sherborne B, Cooper I (2002) Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res. 19 1446-1457. 

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. 

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