Interaction with food

The presence of food may influence the absorption of drugs and can either enhance, delay or reduce absorption77. The most serious problem with such studies is that variations in drug absorption may be due to several different effects. Primarily, the effect of food on gastric emptying is considerable, and variations in the rate at which food is presented to the small intestine will change the drug pharmacokinetics. Secondly, the drug can interact with the food in the intestinal lumen, adsorb to food or be or absorbed by it. Metal ions present in food such as milk can chelate drug, or the drug can bind to dietary proteins thus changing its bioavailability. The presence of viscous chyme can act as a physical barrier reducing drug access to the absorbing surface. Finally, food may influence the absorption process by direct interference with the epithelial biochemistry; for example the absorption of a drug that was taken up actively by a carbohydrate transport system would be slowed in the presence of a large carbohydrate meal which would compete for the transporter. In practise it is extremely difficult to disentangle these factors and so most studies simply report an overall effect.

The absorption of drugs such as penicillin V and G, theophylline and erythromycin is reduced by the presence of food, but food delays the absorption of other drugs (cimetidine, metronidazole and digoxin). The effect of food on drug absorption can be dependent on the type of dosage form used, the excipients and the form of the drug, for example erythromycin stearate in film coated tablets demonstrated reduced absorption with food, erythromycin estolate in suspension was unaffected by food, but absorption of erythromycin ethylsuccinate in suspension and erythromycin estolate in capsules was increased by the presence of food77. A co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related

Figure 6.14 Absorption profile for a drug which is poorly absorbed from the colon when administered in a zero-order sustained release dosage form

Figure 6.14 Absorption profile for a drug which is poorly absorbed from the colon when administered in a zero-order sustained release dosage form antiarrhythmic agent, disopyramide78. It was postulated that this was due to the bidisomide being well absorbed in the upper but not lower small intestine.

Certain components of food, notably fibre, have a particularly important effect on drug absorption. Fibre is known to inhibit the absorption of digoxin and entrap steroids. It is well accepted that foods such as milk products, which have a high content of polyvalent metals such as calcium, magnesium, iron, aluminium and zinc, inhibit the absorption of tetracycline and reduce availability. Doxycycline has a slightly lesser tendency to form chelates, thus milk reduces its bioavailability somewhat less than other tetracyclines.

Availability of many drugs is determined by their solubility at the local pH. In the stomach this is highly variable, depending on the presence of food, but the small intestine has a relatively constant pH around 7.0. Drug absorption may be modulated by the presence of food which alters the gastric pH, the viscosity and the transit time through various sections of the gut and a single clear effect may not be evident.

Grapefruit juice greatly increases the bioavailability of certain drugs such as lovastatin and simvastatin, but not pravastatin79. The increase in bioavailability probably results from downregulation of CYP3A4 in the small intestine80. Hence large amounts of grapefruit juice should be avoided, or the dose of affected drugs should be reduced accordingly. The effect appears to be specific to grapefruit juice, since it cannot be reproduced with other citrus juices such as orange juice. It has been suggested that the inhibitory effect of grapefruit juice may be partially counteracted as it may also activate P-glycoprotein efflux of some drugs81

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