Blood Flow

The entire GIT is highly vascularized and therefore well perfused by the bloodstream. The splanchnic circulation, which perfuses the GIT, receives about 28% of cardiac output, and this flow drains into the portal vein and then goes to the liver prior to reaching the systemic circulation. An absorbed drug will first go to the liver, which is the primary site of drug metabolism in the body; the drug may be metabolized extensively prior to systemic distribution. This has been referred to as the hepatic "first-pass" effect, or presystemic hepatic elimination, and it has important implications in bioavailability and drug therapy.

The fact that the GIT is so well perfused by the bloodstream permits efficient delivery of absorbed materials to the body. As a result of this rapid blood perfusion, the blood at the site of absorption represents a virtual sink for absorbed material. Under normal conditions, then, there is never a buildup in drug concentration in the blood at the site of absorption. Therefore, the concentration gradient will favor further unidirectional transfer of drug from the gut to the blood. Usually, then, blood flow is not an important consideration in drug absorption. Generally, the properties of the dosage form (especially dissolution rate) or the compound's inherent membrane permeability will be the limiting factors in absorption.

There are circumstances, however, where blood flow to the GIT may influence drug absorption. Those compounds absorbed by active or specialized mechanisms require membrane participation in transport, which in turn depends on the expenditure of metabolic energy by intestinal cells. If blood flow and therefore oxygen delivery is reduced, there may be a reduction in absorption of those compounds.

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 animals (113-115). The absorption rate of tritiated water, which is rapidly absorbed in 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. These relationships are illustrated in Figure 16.

An interesting clinical example of the influence of blood flow on drug absorption is that provided by Rowland et al. (116). After oral ingestion of aspirin, one subject fainted while blood samples were being taken. Absorption ceased at the time of fainting, but continued when the subject recovered. Interestingly, there was no reduction in the total amount of aspirin absorbed compared with another occasion when the subject did not faint. Another investigator observed a three-hour delay in the absorption of sulfamethoxypyridazine in a patient who fainted (117). The most reasonable explanation for these observations is the fact that in a fainting episode blood is preferentially shunted away from the extremities and other body organs, including the GIT, thereby reducing blood perfusion of the tract and resulting in a decreased rate of absorption (sink conditions no longer apply). It is possible that generalized hypotensive conditions may be associated with altered drug absorption. In that regard, the influence of congestive heart failure and other disease conditions that will alter GIT blood flow as well as the presence of other drugs that may alter flow need to be considered. For

(A) Mesenteric (B) Intestinal

Blood Flow, ml/min Blood Flow, ml/min g

Figure 16 (A) Absorption rate constant of sulfaethidole in dogs as a function of mesenteric blood flow. (B) Absorption rate of several compounds in rats as a function of intestinal blood flow. Source: Part A based on data from Ref. 115 and part B based on data from Ref. 114.

(A) Mesenteric (B) Intestinal

Blood Flow, ml/min Blood Flow, ml/min g

Figure 16 (A) Absorption rate constant of sulfaethidole in dogs as a function of mesenteric blood flow. (B) Absorption rate of several compounds in rats as a function of intestinal blood flow. Source: Part A based on data from Ref. 115 and part B based on data from Ref. 114.

example, it has been suggested that digoxin absorption is impaired in congestive heart failure but improves after compensation (118). The influence of such conditions on absorption has been reviewed elsewhere (119), but there is relatively little information available.

Blood flow to the GIT increases shortly after a meal and may last for several hours. Digestive processes in general seem to enhance blood flow to the tract. For reasons discussed previously, however, coadministration of a drug with a meal would normally not be expected to improve drug absorption on the basis of increased blood flow. Strenuous physical exercise appears to reduce blood flow to the tract and may reduce absorption rate.

COMPLICATING FACTORS IN DRUG ABSORPTION Drug Interactions: Physical-Chemical Factors

A variety of factors may affect the rate or extent of absorption. Interactions in absorption are mediated by physical-chemical, physiological, or biochemical factors. Physical-chemical considerations include the characteristics of the dosage form and altered solubility, dissolution, and chemical stability within the GIT. Physiological factors include residence time in the tract (i.e., gastric-emptying and intestinal transit rates) and blood flow to the absorbing membrane as well as its characteristics. Biochemical factors would include enzymatic activity in the GIT. Drug-food and drug-drug interactions may alter absorption by one or more of the foregoing mechanisms.

As discussed previously, drug absorption may be impaired or improved when food is present in the GIT. Food may reduce the rate or extent of absorption by virtue of reduced gastric-emptying rate, which is particularly important for compounds unstable in

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