Drug interactions are unintended effects that can happen when two or more substances are consumed togetherâfor example, when one drug is taken in combination with another drug, or when a drug is taken along with a certain food, phytochemical, beverage or herb. Many drug interactions involve problems with the way the drug is absorbed, metabolized or eliminated from the body. The interactions can be grouped into two broad categories: those that reduce absorption of the drug, thus decreasing drug bioavailability, and those that amplify absorption, increasing bioavailability.1 (A third type of nutrient-drug interaction involves ways in which drugs impair the body?s absorption of nutrients or otherwise affect nutritional status, an important topic that is beyond the scope of this article.)
The P-450 enzymes effect
One way phytochemicals can decrease or increase drug bioavailability is by impacting the cytochrome P-450 enzyme system. The CYP family of enzymes plays an essential role in drug metabolism and the detoxification of harmful substancesâacting primarily in the liver and, to some extent, in the intestines and various other cells in the body. CYP isoenzymes, for example, play a key role in first-pass metabolism, the process by which a substance is absorbed through the gastrointestinal tract. The most abundant of the CYP isoenzymes, CYP3A4, contributes to the first-pass metabolism of approximately half of all drugs prescribed.2
Thus, substances that induce or inhibit the activity of CYP3A4 isoenzymes are of particular importance. Substances that induce CYP3A4 activitiesâor those of other CYP isoformsâencourage the body to make more enzymes available for action, reducing drug bioavailability by enhancing or accelerating drug clearance from the body and decreasing its concentration. Substances that inhibit the activity of CYP increase bioavailability by lessening drug metabolism and clearance, possibly resulting in extended drug effects and elevated or even toxic levels of that drug in the body.
There is some evidence, for reasons that are not yet clear, that women naturally generate higher levels of CYP3A4 than men, giving them more efficient clearance of certain drugs metabolized via CYP3A4.2 In one study, researchers found twofold higher levels of CYP3A4 and a corresponding 50 percent increase in clearance of verapamil (an antihypertensive drug) in the livers of women, compared with men.2 Further research is needed to reveal the mechanisms at play, but this phenomenon promises to have important implications for the future.
Grapefruit juice and CYP enzymes
Grapefruit juice has achieved a certain notoriety following the accidental discovery, in 1991, that it has a powerful ability to inhibit CYP enzymes, and thus the potential to cause food-drug interactions.3 Research has since confirmed that grapefruit juice increases the bioavailability of numerous drugs by inhibiting CYP3A4 first-pass effects in the small intestine.3,4,5 The formerly innocuous breakfast beverage is now known for its potential to elevate blood levels of a long list of drugs (see sidebar). Initially, researchers believed that the flavonoids naringin and quercetin caused CYP inhibition effects, but newer research suggests that constituents known as 6?,7?-dihydroxybergamottin and bergamottin are most likely responsible.6,7,8
One glass of grapefruit juice seems to be enough to achieve maximum interaction potential.3 However, reports of toxicity or other clinical problems resulting from grapefruit juice-drug interactions are actually quite rare, and some researchers have suggested that the true incidence of grapefruit juice-drug interactions is very low.9 This is due at least in part to individual differences in rates of intestinal CYP metabolism.9 Nonetheless, caution seems warranted, especially for drugs with a narrow therapeutic index (described by a ratio of the dose that will cause toxicity to the dose needed to achieve therapeutic effects). Some research suggests that elderly people may be particularly susceptible to grapefruit-induced interactions.10
Whole grapefruit has been shown to have the same effect on CYP3A4 as the juice.5 Other citrus fruits, including bitter orange (Citrus aurantium) and sweet orange (C. sinensis), have demonstrated no effect on CYP, perhaps because neither contain the 6?,7?-dihydroxybergamottin found in grapefruit.6,11,12 However, calcium-fortified orange juice presents an interaction potential of its own (see ?Minerals? later in this article).
Herbs and CYP enzymes
In 2000, St. John?s wort (Hypericum perforatum) made headlines when researchers announced that the herb reduced blood concentrations of indinavir (a protease-inhibitor drug used to treat HIV infection), possibly by inducing CYP3A4 activity.13 Other clinical reports associated the herb with reduced blood levels of cyclosporine (used to prevent organ transplant rejection), digoxin (used to treat congestive heart failure), and theophylline (an asthma treatment).14,15,16,17 On the other hand, in one study involving healthy volunteers, St. John?s wort had no effect on blood levels of carbamazepine (an anticonvulsant that also induces CYP3A4).18 However, subsequent research confirmed that St. John?s wort does have the potential to affect drug metabolism by inducing intestinal and hepatic CYP3A4.19,20
These discoveries sparked interest in other herbs? potential to interfere with CYP-mediated drug metabolism and prompted a spate of additional investigations. Since then, kava (Piper methysticum) extract has been shown to induce CYP3A4, and certain isolated and purified kavalactone compounds induced CYP3A23.21 In a laboratory study, the plant sterol guggulsterone from the herb guggul (Commiphora mukul) induced expression of CYP3A genes in mouse and human liver cells.22 Echinacea (E. purpurea) tincture has been shown to inhibit some CYP enzymes in vitro, but in vivo studies have yielded conflicting results. One study involving 12 healthy volunteers concluded that in the body, echinacea reduced clearance of a drug metabolized by CYP1A2, had no effect on clearance of drugs metabolized by CYP2C9 or CYP2D6, and affected the metabolism of some but not all CYP3A substrates.23 However, results of another recent study suggest that echinacea has no effect on CYP activity (including CYP3A4) and poses negligible risk of causing drug interactions.11 The clinical significance of all of these findings is unknown.
A number of other popular botanicals have demonstrated no effect on CYP activity. Standardized eleuthero extract (Eleutherococcus senticosus), decaffeinated green tea extract (Camellia sinensis), milk thistle (Silybum marianum), saw palmetto (Serenoa repens) and valerian (Valeriana officinalis) all had little or no effect on CYP3A4 or CYP2D6 isoforms in preliminary studies involving healthy volunteers.11,24,25,26,27 Clearly, much more research is needed before definitive conclusions can be made about the interaction potential of botanicals. Caffeine, an alkaloid that occurs naturally in botanical products such as coffee (Coffea arabica), cocoa (Theobroma cacao), tea and guarana (Paullinia cupana), is known to induce the CYP1A2 isoenzyme and is often used as a ?probe? in studies to assess the metabolic activity of CYP isoforms.28 Caffeine increases blood levels and impairs clearance of theophylline from the body, which may enhance the effectiveness of the drug but also increases caffeine side effects such as nervousness, tremor and sleeplessness.29
Supplemental fiber products can significantly delay the absorption of drugs and nutrients, including vitamins and minerals.30 Bulk-forming laxatives, such as psyllium-based products, should be consumed at least two hours before or after taking medication to prevent problems.31 People taking digoxin are advised to avoid taking their medication along with bran fiber, bulk-forming fiber-based laxatives, and foods that contain pectin (like apples and pears) because these substances may bind to the drug, lowering concentrations and reducing therapeutic effects.1,29
Minerals can form complexes or chelates with drugs, creating insoluble structures that are difficult for the body to absorb.29 Calcium, in particular, has been implicated in a variety of interactions with antibiotics. Calcium-fortified orange juice has been shown to cause chelation interactions with the fluoroquinolone antibiotics ciprofloxacin, gatifloxacin and levofloxacin. In studies involving healthy volunteers, coadministration of calcium-fortified orange juice lowered blood concentrations of these three drugs.32,33,34 The antibiotic tetracycline also forms chelates with calcium and should not be consumed with dairy products or calcium supplements (or over-the-counter antacids, which are high in calcium).1,29 In addition to calcium, tetracyclines may bind with aluminum, magnesium and other minerals.1,35
Lastly, calcium carbonate (commonly found in antacids and certain supplements) binds with and interferes with the absorption of the thyroid hormone levothyroxine, an interaction that may be particularly significant for postmenopausal women taking both agents at the same time.36 To be on the safe side, calcium carbonate should be taken at least four hours before or after the medication.
Iron also forms complexes with the antibiotic ciprofloxacin, the quinolone antibiotics nalidixic acid and norfloxacin, and the drug levodopa (used to treat Parkinson?s disease), in all cases reducing absorption and peak blood concentrations of the drug.1,29 Copper, magnesium, manganese and zinc all have been reported to have similar effects on quinolone antibiotics.1 Magnesium hydroxide has been reported to increase the absorption of the analgesic ibuprofen, possibly because it elevates gastric pH.1
Vitamins, so important for optimal health, have the potential to interfere with the way certain drugs work. Vitamin K, for example, is essential for healthy blood clotting, but neutralizes the blood-thinning effects of anticoagulant drugs such as warfarin.1,29 Foods rich in vitamin K include broccoli, brussels sprouts, kale, parsley and spinach, as well as coffee, green tea and liver. Vitamin B6, also known as pyridoxine, reduces blood levels of levodopa.1,35
Tyramine-containing foods and MAOs
A particularly dangerous food-drug interaction is the hypertensive crisis that can occur when foods rich in tyramine are consumed in combination with antidepressant drugs known as monoamine oxidase inhibitors. Tyramine, a phenolic amino acid derived from tyrosine, is normally inactivated by the naturally occurring enzyme MAO, but it accumulates in the presence of MAO inhibitors. An accumulation of tyramine can lead to sudden and dangerous elevations in blood pressure. Elevated tyramine concentrations are present in high-protein foods that have been aged, fermented, pickled, smoked or bacterially contaminated, as well as in some alcoholic beverages.1,29 Some examples of foods to avoid include aged cheese, fava beans, fermented foods (such as salami or pepperoni), pickled fish, red wines and some beers. While newer antidepressants, such as the selective serotonin reuptake inhibitors, have largely supplanted the use of MAO inhibitors, drugs with MAO inhibitor effects are still available and thus the potential for interaction is worth noting.
Foods that affect urinary pH and excretion
Food-related changes in urinary pH can alter the rate of drug excretion by either extending or decreasing a drug?s elimination half-life (the time required for half of the drug to be excreted from the body). The half-life of an acidic drug will be lengthened in acidic urine, but decreased in alkaline urine. Foods that acidify the urine include cheese, eggs and meat, while citrus and vegetables have alkalinizing effects.29
A diet high in salt can increase the urinary excretion of lithium, a drug used to treat bipolar disorder. Sodium competes with lithium in the kidneys, thereby accelerating excretion of the drug.29
Other effects on absorption
Some drugs should be taken with food simply to prevent drug-related stomach irritation. However, the mere presence of food in the stomach has the potential to enhance or impair drug absorption. The presence of food, for example, can enhance the bioavailability of the antihypertensive drugs hydralazine, metoprolol and propranolol, as well as the cholesterol-lowering drug lovastatin.1,29 On the other hand, the presence of food in the stomach has been reported to decrease absorption of the antibiotics ampicillin, azitromycin, erythromycin, penicillin and tetracycline, as well as alendronate (an osteoporosis treatment), levodopa, levothyroxine and other drugs.29,35
In general, fatty foods delay gastric emptying, lengthening the amount of time needed for a drug to reach peak blood levels.1 This does not mean that less drug will be absorbed, however. High-fat meals can enhance the absorption of griseofulvin (an antibiotic), itroconazole (an antifungal), lovastatin and saquinavir (a protease inhibitor used to treat HIV infection), among others.1,35 High-carbohydrate meals, on the other hand, are reported to decrease the absorption of erythromycin, levodopa, most penicillins and tetracycline.35 These are best taken on an empty stomach, unless otherwise directed.29
Nutrient-drug interactions are not a new phenomenon. While much is known about the ways foods and nutrients can impact the effects of drugs, our understanding of the topic and its clinical significance is still evolving. Future research will likely reveal more ways in which nutrients can interact with drugs, but more important, should also shed light on the actual incidence and the practical implications of such interactions. In the meantime, a dose of caution with the drug-nutrient interactions we already know aboutâand a glass of water to wash down medications, unless otherwise directedâseem to be the prudent path.
Evelyn Leigh is a free-lance writer and natural products industry consultant in Boulder, Colo.
1. D?Arcy PF. Nutrient-drug interactions. Adverse Drug React Toxicol Rev 1995;14(4):233-54.
2. Wobold R, et al. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology 2003;38:978-88.
3. Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability: mechanism, extent and relevance. European J Clin Nutr 2004;58(1):1-9.
4. Lown KS, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997;99(10):2545-53.
5. Bailey DG, Dresser GK. Grapefruit-lovastatin interaction. Clin Pharmacol Ther 2000;67(6):690.
6. Edwards DJ, et al. Identification of 6?,7?-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Disposition 1996;24(12):1287-90.
7. Paine MF, et al. Two major grapefruit juice components differ in intestinal CYP3A4 inhibition kinetic and binding properties. Drug Metab Disposition 2004 Oct. 14 [Published online ahead of print: jpet.aspetjournals.org/cgi/content/]
8. Schmiedlin-Ren P, et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Drug Metab Disposition 1997;25(11):1228-33.
9. Huang SM, et al. Drug interactions with herbal products and grapefruit juice: a conference report. Clin Pharmacol Ther 2004;75(1):1-12.
10. Dresser GK, et al. Grapefruit juice-felodipine interaction in the elderly. Clin Pharmacol Ther 2000;68(1):28-34.
11. Gurley BJ, et al. Assessment of botanical supplementation on human cytochrome P450 phenotype: citrus aurantium, echinacea, milk thistle, saw palmetto. Clin Pharmacol Ther 2004;75(2):35.
12. Takanaga H, et al. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P4503A4. Pharmacol Exp Ther 2000;293(1):230-6.
13. Piscitelli SC, et al. Indinavir concentrations and St. John?s wort. Lancet 2000;355:547-8.
14. Barone GW, et al. Drug interaction between St. John?s wort and cyclosporine. Ann Pharmacother 2000; 34(9):1013-6.
15. Johne A, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John?s wort. Clin Pharmacol Ther 1999;66:338-45.
16. Nebel A, et al. Potential metabolic interaction between St. John?s wort and theophylline. Ann Pharmacother 1999;33:502.
17. Ruschitzka F, et al. Acute heart transplant rejection due to St. John?s wort. Lancet 2000;355:548-9.
18. Burstein AH, et al. Lack of effect of St. John?s wort on carbamazepine in healthy volunteers. Clin Pharmacol Ther 2000; 68(6):605-12.
19. D?rr D, et al. St. John?s wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP34A. Clin Pharmacol Ther 2000;68(6):598-604.
20. Markowitz JS, et al. Effect of St. John?s wort on drug metabolism by induction of cytochrome P4503A4 enzyme. JAMA 2003;290(11):1500-4.
21. Ma Y, et al. Desmethoxyangonin and dihydromethysticin are two major pharmacological kavalactones with marked activity on the induction of cytochrome P4503A23. Drug Metab Disposition 2004 Jul 28. [Published online ahead of print: jpet.aspetjournals.org/cgi/content/]
22. Brobst DE, et al. Guggulsterone activates multiple nuclear receptors and induces CYP3A4 gene expression through the pregnane X receptor. J Pharmacol Exp Ther 2004;310(2):528-35.
23. Gorski JC, et al. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther 2004;75:89-100.
24. Donovan JL, et al. Siberian ginseng (Eleutherococcus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Disposition 2003;31(5):519-22.
25. Donovan JL, et al. Green tea (Camellia sinensis) extract does not alter cytochrome P-450 3A4 or 2D6 activity in healthy volunteers. Drug Metab Disposition 2004; Jun 9. [Published online ahead of print: jpet.aspetjournals.org/cgi/content/]
26. Markowitz J, et al. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P4502D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther 2003;74(6):1-2.
27. Donovan JL, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Disposition 2004;32:1333-6.
28. Bendriss E, et al. Liquid chromatographic method for the simultaneous determination of caffeine and fourteen caffeine metabolites in urine. J Chromatography 2000;746:331-8.
29. O?Brien D, Haddad AR. Counseling patients on drug-food interactions. US Pharmacist 1997;22(6):1-8.
30. Blumenthal M. Interactions between herbs and conventional drugs: introductory considerations. HerbalGram 2000; 49:52-63.
31. Kuhn M. Herbal remedies: drug-herb interactions. Critical Care Nurse 2002;22(2):22-30.
32. Wallace AW, et al. Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers. J Clin Pharmacol 2003;43:539-44.
33. Amsden GW, et al. Lack of bioequivalence of levofloxacin when coadministered with a mineral-fortified breakfast of juice and cereal. J Clin Pharmacol 2003;43:990-5.
34. Wallace AW, et al. Lack of bioequivalence of gatifloxacin when coadministered with calcium-fortified orange juice in healthy volunteers. J Clin Pharmacol 2003;43:92-6.
35. Brown C. Overview of drug interactions. US Pharmacist 2000;25(5):1-14.
36. Singh N. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000;282:2822-25.
37. Thomas JA, Burns RA. Important drug-nutrient interactions in the elderly. Drugs & Aging 1998;13(30:199-209.
Natural Foods Merchandiser volume XXVI/number 2/p. 42, 44