Secondary Factors Influencing Drug Absorption 441 Biological Factors of Gastrio Intestinal Tract

GI tract plays important roles in secretion, digestion, and absorption. Many biological factors, such as gastric emptying, gastric and intestinal pH, GI content, GI motility, GI surface area, and blood flow (Fleisher et al., 1990) can affect drug absorption.

4.4.1.1 Gastric Emptying Time

Gastric emptying time refers to the time needed for the stomach to empty the total initial stomach contents. During digestion, gastric emptying depends on the tone of proximal stomach and pylorus, which is under reflex and hormonal control. Generally, anything that slows down gastric emptying is likely to slow down the rate (not extent) of drug absorption, and thus affect onset of the therapeutic response. A lot of factors promote gastric emptying, such as hunger, lying on right side, noncaloric liquid intake, drugs (metoclopramide, prokinetic drugs), and some excipients. On the other hand, factors, such as meals (especially with fatty, bulky, and viscous food), lying on left side, and other drugs (tricyclic antidepressants, anticholin-ergics, and alcohol) retard gastric emptying. Gastric emptying of solution-type dosage forms and suspensions of fine drug particles is generally much faster and less variable than that of solid, nondisintegrating dosage forms and aggregated particles. For drugs with high solubility and high membrane permeability, gastric emptying rate will control the absorption rate and onset of the drugs. There will be a direct relation between gastric-emptying rate and maximal plasma concentration, and an inverse relation between gastric-emptying rate and the time required to achieve maximal plasma concentrations.

4.4.1.2 Surface Area

Surface area of different regions of GI influences drug absorption. Small intestine has largest effective surface area for drug absorption due to the presence of folds of mucosa, villi, and microvilli. For carrier-mediated drug absorption, small intestine is also the most important region for most drug transporters that are also expressed in this area. In contrast, stomach and large intestine have no villi, microvilli, or less transporter expression.

4.4.1.3 GI Transit Time

GI transit time or mean resident time (MRT) can also influence oral drug absorption. Increase in the GI residence time (or decrease of motility) leads to enhanced drug absorption potential. Stomach MRT is about 1.3 h while the small intestine MRT is around 3h. The longer MRT in small intestine will contribute to a higher drug absorption potential.

4.4.1.4 Intestinal Motility

Intestinal motility is another factor that influences oral drug absorption. Intestinal movement includes propulsion and mixing. Propulsive movement determines the intestinal transit time and is important for slow release dosage forms, enteric-coated drug that is only released in intestine, slowly dissolving drugs, and carrier-mediated absorption. Mixing movement increases dissolution rate where the drug molecule contacts with endothelial surface area for absorption.

4.4.1.5 Components, Volume, and Properties of Gastrointestinal Fluids

Components, volume, and properties of gastrointestinal fluids especially GI pH will change the drug's ionization, solubility, dissolution rate, and therefore affect drug absorption. The rate of dissolution from a dosage form, particularly tablets and capsules, is dependent on pH. Acidic drugs dissolve most readily in alkaline media and will have a greater dissolution in the intestinal fluids than in gastric fluids. Basic drugs will dissolve most readily in acidic solution, and thus the dissolution will be greater in gastric fluids than in intestinal fluids. GI pH depends on general health of the individual, disease conditions, age, type of food, and drug therapy. Antichlolinergic drugs and H2-blockers increase gastric pH and significantly decrease bioavailability of some weakly basic drugs with pH-dependent solubility.

Food influences drug absorption in different ways. High fat food may stimulate bile salt secretion, increases drug solubility and dissolution, and increases bioavailability for certain drugs with low solubility. High protein may increase gastric pH, thus decrease dissolution of weak basic drugs and bioavailability. High calorie food decreases gastric emptying rate, delays the rate of absorption, and delays the onset of therapeutic drugs. At the same time, food components may compete for drug absorption that is mediated by transporters. For instance, grapefruit juice inhibits efflux pump (P-gp) and increases bioavailability of P-gp substrates. In addition, food components may form complex with drugs (complex-ation) and decrease drug absorption and bioavailability as seen in the example that tetracycline forms a complex with calcium in milk to hinder its absorption.

4.4.1.7 Blood Flow

Blood flow in the GI tract also plays an important role in drug absorption. GI tract is highly vascularized and receives 28% of the cardiac output. The higher blood flow promotes the higher drug absorption, especially for those active-absorption mediated and highly permeable drugs.

Age can also influence the drug absorption. Newborns, for example, have less acidic gastric fluids, smaller gut fluid volume, slower gastric emptying rate, less intestinal surface area and blood flow, and thus have relatively lower drug absorption.

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