E-DRUG: meals and medicines
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[Tables not included]
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Beverley Snell
Senior Fellow
Centre for International Health
Macfarlane Burnet Institute for Medical Research & Public Health
GPO Box 2284, Melbourne 3001 Australia
http://www.burnet.internationalhealth.edu.au
Telephone 613 9282 2115 / 9282 2275
Fax 61 3 9282 2144 or 9282 2100
Time zone: 10 hours ahead of GMT.
email <bev@burnet.edu.au>
Site: Alfred Medical Research & Education Precinct (AMREP),
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Australian Prescriber
40 | Volume 29 | Number 2 | April 2006
http://www.australianprescriber.com
Meals and medicines
Andrew McLachlan and Iqbal Ramzan, Faculty of Pharmacy, University of
Sydney, NSW\
Associate Professor McLachlan and Associate Professor Ramzan have
acted as consultants to the pharmaceutical industry and are members
of the Pharmaceutical Subcommittee of the Australian Drug Evaluation
Committee (ADEC).
Summary
Food and its constituents may have a significant effect on both the
rate and extent of absorption of drugs after oral administration.
Understanding the effect of meals on medicines enables health
professionals to advise patients about taking medicines with or
without food. Co-administration of drugs with food generally delays
drug absorption. However, meals may have a variable effect on the
extent of absorption- depending on the characteristics of the meal,
the drug and its formulation. Some drugs have strict guidelines about
when they should be taken in relation to meals. Generally, patients
should be advised to take their medicines consistently at the same
time with respect to meals.
Key words: bioavailability, drug interactions, food.(Aust Prescr 2006;29:40-2)
Introduction
Understanding the possible clinical implications of taking medicines
with or without a meal is important for achieving quality use of
medicines. Although the effect of food is not clinically important
for many drugs, there are food-drug interactions which may have
adverse consequences. Often these interactions can be avoided by
advising the patient to take their medicines at the same time with
respect to meals.
The effect of food on absorption
The formulation of a drug influences its absorption. Food can affect
both the rate and extent of absorption (Table 1).
Rate of absorption
Meals slow down gastric emptying and this can delay drug absorption.
The composition of the meal influences the rate of gastric emptying -
high fat meals lead to delayed gastric emptying. A delay in the drug
reaching the small intestine can delay its subsequent absorption into
the systemic circulation. Based on these observations, oral
administration of a medicine under fasting conditions is often
recommended when rapid absorption (and hence rapid onset of
therapeutic effect) is needed. For most medicines, especially those
used for chronic conditions, a delay in the onset of absorption is of
no clinical consequence as long as the amount of drug absorbed is
unaffected.
Extent of absorption
Food has the potential to either increase or decrease the extent of
drug absorption. Understanding food-drug interaction mechanisms
enables the clinician to provide appropriate advice to patients about
taking medicines with respect to the timing and composition of meals.
The effect of food depends on the physicochemical and pharmacokinetic
characteristics of the drugs.1 The clinical significance of the
effect will in turn depend on the pharmacodynamic characteristics of
the drug. For example, the poorly water soluble antiretroviral drug
saquinavir should betaken with food to allow bile enhancement of its
dissolution which then facilitates absorption. The extent of
absorption is more than doubled by taking saquinavir after a full
cooked breakfast. Taking saquinavir on an empty stomach reduces its
bioavailability and could lead to therapeutic failure.1 Delayed
gastric emptying after a meal and the associated gastric acid
secretions can reduce the bioavailability of some medicines that are
acid labile. The constituents of a meal may also specifically
interact with drugs (Table 2). Calcium and other cations in food can
form insoluble chelates with some medicines preventing their optimal
absorption. Bisphosphonates are therefore recommended to be taken
with plain water to prevent the formation of chelates which
significantly reduce bioavailability.
Grapefruit juice: an important example
Co-ingestion of grapefruit juice and certain drugs (Table 3)
significantly increases their bioavailability because the
constituents of the juice inhibit pre-systemic drug metabolism or
transport. This increase in bioavailability can lead to excessive
beneficial or adverse effects.2 The effects of grapefruit juice are
complex and have been widely studied.3, 4 A single glass of
grapefruit juice is enough to increase the bioavailability of some
drugs. If the juice is drunk over several days the effects are
long-lasting3,4, so simply separating the dose of medicine and the
ingestion of grapefruit juice does not prevent the interaction. For
this reason grapefruit juice ingestion should be avoided completely
with certain drugs, for example cyclosporine. Could grapefruit juice
be routinely used to enhance the bioavailability of some medicines?
The answer would appear to be no because the effect of grapefruit
juice on drug absorption is highly variable. It depends on the
constituents of the juice, how it is prepared and varies with brands
and batches.| Grapefruit juice is not 'pharmaceutical grade' or
consistently ofthe same 'quality', so co-administration with a drug
would leadto a variable response.
Studying the effect of food
The product information approved by the Therapeutic Goods
Administration is the main source of information about the possible
effects of food on drug absorption. This information is generally
derived from a 'food effect study' that is conducted during drug
development. Typically, this involves a randomized cross-over single
dose pharmacokinetic study in healthy people. They take the drug of
interest after an overnight fast and also after a standard high fat
breakfast. This design is meant to examine the effect of food under
'extreme' conditions. Unfortunately, a volunteer eating a high fat
meal does not necessarily reflect the circumstances of the patients
who will take the drug. Dosing recommendations with respect to food
derived from these studies may therefore not provide the best guide
to the actual impact of food on drug absorption.
Taking medicines with meals to help adherence, tolerability and efficacy
Prescribing a drug regimen that fits in with the patient's daily
routine (which is usually centred around mealtimes) can enhance the
patient's adherence to treatment. This leads to the general
recommendation that patients should take their medicines at
prescribed and consistent times relative to their meals. This is
despite the fact that the absorption of some medicines may be
significantly reduced when taken with food, for example atorvastatin
and thyroxine. Patients should also be informed if particular foods
can interfere with their treatment(Table 2).Some medicines (for
example non-steroidal anti-inflammatory drugs and metformin) are
taken with food to minimise the risk of gastrointestinal adverse
effects. Repaglinide and the sulfonylureas should be taken before a
meal to avoid the risk of significant hypoglycaemia. In the case of
repaglinide, if a meal is skipped then the drug dose should also be
skipped. Similarly, taking acarbose with meals is essential to ensure
its maximum efficacy in delaying the intestinal absorption of
carbohydrates.
Conclusion
Meals may have variable and often unpredictable effects on drugs via
a range of mechanisms. By understanding and appreciating the clinical
consequences of these effects health professionals can provide advice
about the appropriate nessof ingesting medicines with respect to the
times and the composition of meals. The provision of timely and
appropriate advice about the possible effects of meals on medicines
and the importance (or lack) of the timing of meals and medicines is
an important issue impacting on the quality use of medicines.
References
1. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs2002;62:1481-1502.
2. McNeece J. Grapefruit juice interactions. Aust Prescr 2002;25:37.
3. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug
interactions. Brit J Clin Pharmacol 1998;46:101-10.
4. Dahan A, Altman H. Food-drug interaction: grapefruit juice
augments drug bioavailability - mechanism, extent and relevance. Eur
J Clin Nutr 2004;58:1-9.
Further reading
Birkett DJ. Pharmacokinetics made easy. 2nd ed. Sydney:McGraw-Hill; 2002.
Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD.
Herb-druginteractions: an evidence based approach. Curr Med Chem
2004;11:1513-25.
Fugh-Berman A. Herb-drug interactions. Lancet 2000;355:134-8.