Effect of Meal Intake on Drug and Nutrient Absorption
Concurrent meal intake and drug administration can influence oral absorption of drugs and nutrients, and is an example of type II interactions. The overall impact may include changing the rate of absorption, changing the magnitude of absorption, or both. The mechanisms affecting drug or nutrient absorption with concurrent meal intake usually involve one or more of the following factors: (a) altering gastric acid and gastrin secretion, (b) altering gastrointestinal transit time, (c) changing dissolution of drugs in solid dosage forms, (d) binding or complexation of micro- or macronutrient with food contents, and (e) changing bile flow (
25,
26,
27).
Meal intake generally stimulates gastric and intestinal secretions (
28,
29), which theoretically favor drug dissolution from their solid dosage form and facilitate absorption. Meals with higher fat content stimulate the release of bile salts, which also facilitate the intestinal uptake of drugs that are more lipophilic (
30). Furthermore, high-fat meals promote the release of cholecystokinin, which slows GI motility and increases the contact time between the drug molecules and the intestinal epithelial tissues (
31). All these factors combined tend to favor a more complete absorption of certain drugs and nutrients. For example, the oral bioavailability of albendazole and griseofulvin is dramatically increased when taken with a fatty meal (
32,
33). However, the potential physicochemical interactions, the potential binding affinity between the individual drug and food contents, the dose of the drug administered, and the composition of the meals make drug absorption in the presence of food rather erratic and unpredictable. Therefore, concurrent food intake actually contributes to the variation in the magnitude of the drug and nutrient interaction observed (
26). For instance, the data on how food affects the oral bioavailability of verapamil, a calcium channel blocker used in the treatment of hypertension and cardiac arrhythmias, are very inconsistent. A small reduction of verapamil oral bioavailability with concurrent food intake was seen in some studies, whereas a similar number of studies failed to show any clinically relevant change in verapamil bioavailability. Overall, the AUCs of verapamil observed were similar whether it was taken with or without food. The only consistent finding among the studies was that food slowed down the rate of verapamil absorption (
34,
35,
36,
37). These findings suggest that verapamil can be taken without regard to food, as long as it is on a consistent basis.
It is important to differentiate between delayed absorption versus decreased absorption. A delayed absorption of a drug by food does not necessarily lead to a reduced absorption. In many cases, food may impair the rate of drug absorption, as measured by the time required to reach the highest serum drug concentration (or t
max) without affecting the total amount absorbed, as measured by AUC. Delayed absorption of drugs caused by food may be explained by the highly variable physiologic response to feeding among individuals, as well as the inconsistency in food contents consumed between meals. Drugs such as famciclovir, methotrexate, verapamil, levetiracetam, and levodopa have delayed absorption in the presence of food, as measured by increased t
max. However, the total amount absorbed is comparable with or without food, as quantified by the AUCs (
38,
39,
40,
41,
42,
43,
44). In these cases, food can delay the onset of the drug action; however, the efficacy should not be affected. Despite a detectable difference in the pharmacokinetic parameter, these drug-nutrient interactions may not be considered clinically significant. On the contrary, if food intake causes a significant change in the AUC of a drug, it implies that the overall amount absorbed is
reduced. This kind of interaction is more clinically significant, and pharmacodynamic changes may be detected. In this case, patients should receive specific instructions on taking the drug with regard to meal intake. Medication adherence should be emphasized and monitored to warrant stable and consistent drug responses and prevent undesired effects or therapeutic misadventures.
The presence of food causes distention of the stomach and stimulates the autonomic nervous system to alter GI tone (
45,
46). Together with the endocrinologic changes induced by the food contents (e.g., releases of insulin, cholecystokinin, gastrin), splanchnic blood flow is also increased (
47,
48,
49). Increased blood delivery to the liver through the hepatic portal vein can augment presystemic metabolism. However, since the metabolism of most drugs depends primarily on the host’s intrinsic clearance (i.e., the amount and the availability of the drug metabolizing enzymes) but not hepatic blood flow, food-induced augmentation of splanchnic and hepatic blood flow rarely causes clinically significant drug-nutrient interaction. One exception is ethanol, a compound with high extraction ratio whose
metabolism appears to be highly affected by hepatic blood flow. Concurrent food intake with 530 kcal increased the presystemic metabolism of ethanol by up to 49%, with men showing more dramatic increase than women (
50). Hepatic blood flow can be estimated by the use of intravenous indocyanine green (
51).
Tables 103.3 and
103.4 summarize the commonly prescribed medications that should be taken with food or on an empty stomach, respectively.
In summary, whether a drug should be taken with food or on an empty stomach depends mostly on the characteristics of the drug. When in doubt, data and results from the primarily literature should be used to guide clinical decisions. Drugs with decreased oral bioavailability in the presence of food, as suggested by a reduction of AUC, should be taken on an empty stomach. Drugs with delayed, but not decreased, absorption in the presence of food, as described by a change in tmax but no change to AUC, may be taken without regard to meal intake.
Modulation of Gastrointestinal Motility
Gastric emptying and intestinal transit time may alter the rate and magnitude of drug or nutrient absorption from the GI tract. GI motility is regulated by four major components—neurotransmitters present in the enteric nervous system such as acetylcholine, serotonin, and dopamine; gut peptides such as ghrelin, type 1 glucagon-like peptide (GLP1); electrical activity such as pacing and regulation by the interstitial cell of Cajal; and serum blood glucose concentration (
52,
53). Motility of the upper GI tract is increased with hunger. Continued food consumption leads to the release of inhibitory neuroendocrines and peptides, such as GLP1, and cholecystokinin that inhibit gastric emptying and eventually cause satiety (
54,
55,
56). Decreased GI motility increases the contact time for the drug or nutrient with the GI epithelial tissue, thus potentially allows more complete absorption of the drug molecules or nutrients into the portal vein.
The enteric nervous system affects both motility and secretions in the GI tract. Increased GI secretion provides a complementary effect on absorption and the digestive process (
57,
58). Vagal stimulation increases upper GI contraction and decreases pyloric sphincter contractions. As a result, gastric emptying is promoted and the time required for the drug or nutrient to reach the small intestine is shortened. Decreased gastric emptying time may reduce drug absorption because of less complete dissolution (for solid dosage forms) and shortened physical contact time between the drug molecules and the epithelial tissues. Conversely, drug and nutrient absorption may be increased by the coadministration of opioid derivatives, which slow GI motility, or drugs with anticholinergic effect (e.g., sedating antihistamines, phenothiazines, tricyclic antidepressants) that block vagus nerves. However, anticholinergic effects may also decrease secretion in the intestine and affect nutrient absorption. Overall, significantly decreased GI tone may precipitate toxicities because of more complete absorption, whereas elevated GI motility may increase risk of therapeutic failure.
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