Gastric Emptying

Since increased membrane surface area and decreased thickness of the absorbing membrane favor the small intestine rather than the stomach as the primary site for drug

Stomach: pH 1-3 Dudodenum: pH 5-7 Ileum: pH 7-8

Figure 1 Diagrammatic representation of the complexity of the gastro-intestinal tract, with an impression (left) of the size of the GI tract in an adult. The average pH values of the stomach, duodenum, and ileum are shown. The small intestine contains bile salts and other agents, which can affect drug solubility and absorption. The large intestine presents another complexity in the form of the ascending, transverse, and descending colon, so nondisintegrating dosage forms have complex terrains to traverse.

Mouth

Small intestine

Large intestine

Rectum

Salivary glands

Mouth

Salivary glands

Colon Intestine Travese

Figure 1 Diagrammatic representation of the complexity of the gastro-intestinal tract, with an impression (left) of the size of the GI tract in an adult. The average pH values of the stomach, duodenum, and ileum are shown. The small intestine contains bile salts and other agents, which can affect drug solubility and absorption. The large intestine presents another complexity in the form of the ascending, transverse, and descending colon, so nondisintegrating dosage forms have complex terrains to traverse.

Small intestine

Large intestine

Rectum absorption, the rate at which the drug reaches the small intestine can significantly affect its rate of absorption. Hence, gastric-emptying rate may often be the rate-determining step in the absorption of a drug. Light physical activity stimulates stomach emptying, but strenuous exercise delays emptying (1,2). If a patient is lying on his or her left side, the stomach contents have to move uphill to get into the intestine. The emotional state of the patient can either reduce or speed up the stomach-emptying rate (1,2). Numerous pathological conditions may alter gastric-emptying rate (3). Furthermore, drugs administered concomitantly may affect the stomach-emptying rate by themselves influencing GI motility. Any substance in the stomach delays emptying and, therefore, can delay the absorption of some drugs. If the stomach contents differ appreciably in pH, temperature, osmolarity, or viscosity from those conditions normally expected in the intestine, the stomach delays emptying until those conditions approach normal. Food, by altering many of these equilibrium conditions, can affect the rate of stomach emptying. In addition, the volume, composition, and caloric content of a meal can alter the stomach-emptying rate (1,2). Figure 2 illustrates the relationship between the position of a coated controlled-release capsule in the GI tract and plasma concentrations of 4-aminosalicylic acid. This emphasizes the points made earlier. In one case, drug is released in the colon as

Figure 2 Plasma profiles for 4-ASA delivered from a coated capsule designed to target the colon for two different volunteers with different GI transit times. Source: From Refs. 4 and 5.
Figure 3 The effect of fasting and a high fat intake on the plasma concentrations of celcoxib (structure shown) as a function of time. Source: From Ref. 8.

intended, while in the other, the capsule is voided and zero plasma levels are detected (4). Prediction of the rate of absorption in an individual can be difficult, thus it is a problem to predict the range of pharmacokinetic factors that pertains to a large population.

The timing of meals relative to the timing of the oral dosing of a drug can influence the rate, and possibly the extent, of drug availability. It can be anticipated that taking a drug shortly before, after, or with a meal may delay the rate of drug availability as a function of decreased-emptying rate. However, the effect of food on the extent of availability cannot be so readily predicted (6). Food does not always affect drug absorption, one case being that of telbivudine (7). And in the case of celcoxib (Fig. 3), a high fat meal increases the peak plasma levels of the drug and the overall bioavailability.

To understand food effects such as the prolonged retention of the dose form or released drug in the stomach, one must be aware of the acid stability of the drug itself. Erythromycin, for example, is acid labile. Figure 4 illustrates the decreased extent of availability of erythromycin when two 250 mg tablets of erythromycin were taken on a fasting stomach with 20 or 250 mL of water or with 250 mL of water immediately after high-fat, high-protein, and high-carbohydrate meals (9). However, the rate of availability of this poorly absorbed water-soluble, acid-labile antibiotic was not affected by food (i.e., peak time was approximately the same for all dosings), indicating that stomach emptying is not the rate-determining step in the absorption of erythromycin from this drug delivery system. The extent of availability was, however, markedly decreased. This decrease might

Hours

Figure 4 Mean serum erythromycin levels in healthy volunteers given 500 mg of erythromycin stearate with 20 mL of water 250 mL of water (□), or 250 mL of water immediately after a high-carbohydrate meal (o), 250 mL of water immediately after a high-fat meal (•), and 250 mL of water immediately after a high-protein meal (A)- Source: From Ref. 9.

Hours

Figure 4 Mean serum erythromycin levels in healthy volunteers given 500 mg of erythromycin stearate with 20 mL of water 250 mL of water (□), or 250 mL of water immediately after a high-carbohydrate meal (o), 250 mL of water immediately after a high-fat meal (•), and 250 mL of water immediately after a high-protein meal (A)- Source: From Ref. 9.

be due to complexation between drug and food or, more likely, due to degradation of the antibiotic when it is retained in the acid environment of the stomach for longer periods.

A further example of an increase in the extent of availability of a drug taken with food is illustrated in Figure 5. Here the cumulative amount of unmetabolized nitrofurantoin excreted in the urine is plotted against time. Healthy male volunteers took nitrofurantoin as a capsule containing 100 mg of the drug in a macrocrystalline form (circles) and as a tablet containing 100 mg of the drug in the microcrystalline form (squares) (the significance of the macro- and microcrystalline forms are discussed later in this chapter). The dosage forms were taken with 240 mL of water, either on an empty stomach (open symbols) or immediately after a standard breakfast (solid symbols).

It can be seen that food delays the absorption of nitrofurantoin from both the tablet and the capsule dosage forms, as indicated by the initial phase of each plot. However, food enhanced the extent of availability of the drug from both dosage forms, as indicated by the cumulative amount of drug excreted at 24 hours. It appears that delaying the rate of transit of nitrofurantoin through the GIT gives this poorly soluble drug more time to

Figure 5 Mean cumulative urinary excretion of nitrofurantoin after oral administration of a 100-mg macrocrystalline capsule to fasting (O) and nonfasting (•) subjects and a 100-mg macrocrystalline tablet to fasting (□) and nonfasting (■) subjects. Vertical bars represent standard errors of the mean. The macrocrystalline nitrofurantoin (Macrodantin™) was introduced to modify the absorption rate of nitrofurantoin to prevent side effects from high plasma levels. Source: from Ref. 10.

Figure 5 Mean cumulative urinary excretion of nitrofurantoin after oral administration of a 100-mg macrocrystalline capsule to fasting (O) and nonfasting (•) subjects and a 100-mg macrocrystalline tablet to fasting (□) and nonfasting (■) subjects. Vertical bars represent standard errors of the mean. The macrocrystalline nitrofurantoin (Macrodantin™) was introduced to modify the absorption rate of nitrofurantoin to prevent side effects from high plasma levels. Source: from Ref. 10.

dissolve in the GI fluids. Thus, more nitrofurantoin gets into solution and, therefore, more is absorbed.

Hence, food delays stomach emptying and, as a result, may decrease the rate of availability of a drug from its oral dosage form (Fig. 6). The extent of availability of that drug, however, may be increased, decreased, or unaffected by meals. Thus, it is important for patients to be counseled on the importance of the timing of their medications relative to their mealtimes.

A good summary of food effects is given by Schmidt and Dalhoff (11). The most important interactions are those associated with a high risk of treatment failure arising from a significantly reduced bioavailability in the fed state. Such interactions are frequently caused by the following:

1. Chelation with components in food (e.g., alendronic acid, clodronic acid, didanosine, etidronic acid, penicillamine, and tetracycline)

2. Chelation with dairy products (e.g., ciprofloxacin and norfloxacin)

3. Other direct interactions between the drug and certain food components (e.g., avitriptan, indinavir, itraconazole solution, levodopa, melphalan, mercaptopur-ine, and perindopril)

Effect Drug Absorption Food
Figure 6 Schematic of some of the effects of food and liquid intake on drug absorption.

4. Physiological responses to food intake, in particular gastric acid secretion, which may reduce the bioavailability of certain drugs (e.g., ampicillin, azithromycin capsules, didanosine, erythromycin stearate or enteric coated, and isoniazid)

On the other hand, drug bioavailability may be increased because of the following:

1. A food-induced increase in drug solubility (e.g., albendazole, atovaquone, griseofulvin, isotretinoin, lovastatin, mefloquine, saquinavir, and tacrolimus)

2. The secretion of gastric acid (e.g., itraconazole capsules) or bile (e.g., griseofulvin and halofantrine) in response to food intake

For most drugs, such an increase results in a desired increase in drug effect, but in others it may result in serious toxicity (e.g., halofantrine).

The listing of drugs under the categories mentioned earlier can only be understood with reference to the chemical structures of the molecules concerned. Some drugs (such as the tetracyclines) are well known to chelate with divalent ions in particular, such as calcium in dairy products. Chelation often occurs between a keto group and an adjacent hydroxyl, but clearly will depend on the state of ionization of the molecule, hence will be pH dependent. With the tetracyclines there are several opportunities for chelation because of the potential — C=O and C-OH adjacent binding sites. Some other examples are discussed in the following sections. Chelation usually involves the formation of dimers or trimers such that the complex is larger and less well absorbed. There are cases, however, when the chelate is more lipophilic and can enhance absorption.

Chelation with Components in Food

Alendronic acid, clodronic acid, etidronic acid, and other bisphosphonates are implicated in binding to components, for example calcium in food. Their mode of therapeutic action is to bind to hydroxyapatite, which depends on the P-C-P group and the R1 side chain

Table 1 Chemical Structure of Bisphosphonates

O^P-C-P^O

OH Ra OH

Bisphosphonate

R1 side chain

R2 side chain

Etidronatea

+1 0

Responses

  • deodato
    Does Lying left affect gastric emptying time?
    12 months ago
  • ralph burger
    How lying or posture affects drug absorpion?
    9 months ago
  • ida keskitalo
    How gastric emptying decreases the absorption of drug?
    5 months ago
  • Geraldina Li Fonti
    What is effect of gastric emptying time on drug bioavailability?
    23 days ago

Post a comment