Drug Pharmacokinetic Interactions Following Consumption of Plant Products
Part 1 of a series on herb-drug interactions
By Francis Brinker, ND is Clinical Assistant Professor, Department of Medicine, College of Medicine, at the University of Arizona; he is a retained consultant for Eclectic Institute, Inc.
There has been much controversy recently about the potential risks of combining drugs with natural products. In many cases this issue is considered without reference to the tremendous known risks of combining many common drugs. With pharmaceutical medications, the pharmacological activity and mechanism of action are typically known, which makes predicting pharmacodynamic interactions feasible. Drugs with additive effects require careful consideration of dosage management, while combining medicines with antagonistic mechanisms is contraindicated. If a patient is using more than five medications concurrently, it is generally advisable to consult with a pharmacist to avoid potential drug-drug interactions.
The situation with natural products and, in particular, botanical preparations is analogous but less certain. When specific pharmacological activities have been demonstrated in humans for a particular botanical preparation, possible pharmacodynamic interactions can be reasonably predicted and ill-conceived combinations avoided. For example, when herb preparations have known antiplatelet capabilities, it is deemed an unwise risk to use these in significant amounts while taking an anticoagulant medication like warfarin.
On the other hand, additive effects can be desirable when the effect of the primary medication is inadequate. For example, aloe (Aloe vera) juice improved the hypoglycemic effect of glyburide (glibenclamide) when 1 Tbsp of aloe juice was given orally in the morning and at bedtime to 36 diabetes patients for 42 days,1 based on its antihyperglycemic activity when given alone at the same dose and duration.2 Similarly, gurmar (Gymnema sylvestre) leaves enhanced hypoglycemic effects of glyburide and tolbutamide in 22 non-insulin-dependent diabetics given 400 mg/d of a water-soluble acidic fraction of the ethanol extract,3 which alone at this dose also greatly reduced fasting blood glucose in insulin-dependent diabetics.4
Drugs are often prescribed as monotherapy for a particular condition; however, an individual with multiple diseases and/or symptoms frequently receives a variety of medications whose combined effects are uncertain. Likewise, patients self-medicating with over-the-counter remedies often do so without consulting their doctor(s) or pharmacist(s). Research and postmarketing surveillance help predict those combinations that are incompatible. The pharmacokinetic influence on cytochrome P450 (CYP) metabolic enzymes (called isozymes) is being especially examined as a means of understanding how drugs interfere with the bioavailability of other medications. Numerous drugs that act as inducers and inhibitors of CYP isozymes have been well documented, and the list continues to grow.5
Though research has identified the activity of some components in botanicals, this knowledge does not always equate to the combined effects involving other components that influence outcomes. Given that each type of preparation of plant varies in its composition based on the type of processing it undergoes, predicting outcomes becomes even more difficult. The issue of how best to assess how plants and their various preparations impact the bioavailability of pharmaceutical drugs is most challenging. This issue of pharmacokinetic interactions lies outside the normal means of predictability based on known therapeutic applications.
Affecting Absorption by Chemical Binding
Simultaneous consumption is necessary for certain botanical components to bind drugs and reduce or slow their absorption. Simple water-soluble fiber is one example. Guar gum (Cyamopsis tetragonolobus) can be taken to help increase satiation in dieters, to slow gastric emptying to reduce postprandial hyperglycemia, to bind cholesterol in the gut, and for other health purposes.6 However, penicillin absorption is significantly reduced when taken concurrently with 5 g guar gum. This amount of guar gum taken by 10 subjects with digoxin only minimally reduced its urinary excretion compared to placebo fiber, though peak serum levels following a single dose of digitalis were down by 21%.7 When 10 g guar gum was given with metformin to six normal subjects it lowered total absorption and peak serum levels. Nonetheless, postprandial hyperglycemic peak was also reduced with the combination due to the gastric action of the fiber.8
Black tea has traditionally been used for its tannins to precipitate alkaloids and thereby help reduce their absorption in cases of toxic overdoses.9 Iron precipitation in the gut lumen by polyphenols in tea has long been recognized, but recent evidence indicates that herb infusions can also reduce mineral absorption. Inhibition of iron absorption occurs when 200 mL of black tea (Camellia sinensis) is taken with non-hemoglobin sources such as ionic solutions and vegetables.10 Iron absorption is only affected by tea when consumed by mouth simultaneously, due to the formation of iron complexes with tannins in the gut.11 For example, tea reduced absorption of iron in young children who drank 50-750 mL tea daily (average 250 mL), leading to an increased incidence of microcytic anemia.12 Adding milk to black tea does not reduce its inhibition of iron absorption.13
Infusions of 3 g of herbs in 300 mL hot water were prepared using black tea, chamomile (Matricaria recutita), vervain (Verbena officinalis), peppermint (Mentha piperita), pennyroyal (Mentha pulegium), lime flower (Tilia cordata), or cocoa (Theobroma cacao). Each inhibited iron (ferric chloride) absorption: black tea (79-94%), peppermint (84%), pennyroyal (73%), cocoa (71%), vervain (59%), lime flower (52%), and chamomile (47%). This appears to be due to the polyphenolic compounds (tannins, flavonoids or phenolic acids) extracted by water from the herbs.13 Binding of polyphenols, like that of fiber, is a type of chemical binding in the gut that reduces absorption when the interacting elements are taken concurrently. These types of chemical interactions are relatively predictable based on knowledge of the content of these components in plants.
Affecting Metabolism of Drugs with Vegetables
To keep the risk of CYP modulation of drugs with botanical preparations in context, it is useful to consider documented interactions with common foods that affect drug absorption. Cruciferous vegetables (in the cabbage or Brassicaceae, formerly Cruciferae, family) are known inducers of drug metabolism. When either 436 g/d of broccoli, cauliflower, cabbage, and radish sprouts or 500 g/d of broccoli was consumed by 16 subjects, caffeine metabolism by CYP 1A2 was increased.14,15 Regular consumption of Brussels sprouts increases metabolism of warfarin,16 while oxazepam and acetaminophen are more rapidly metabolized in the intestines and/or liver after consuming Brussels sprouts and cabbage.17
Consumption of other umbelliferous vegetables may inadvertently antagonize some of these effects of cruciferous vegetables. Compared to a basal diet with no vegetables, vegetables from the carrot (Apiaceae, formerly Umbelliferae) family consumed for six days significantly decreased CYP 1A2 caffeine metabolism 13-25%. Daily total amounts of 110 g (0.75 cup) frozen carrots, 100 g (1.25 cup) fresh grated parsnips, 50 g (0.5 cup) celery, 5 g (3 Tbsp) parsley, and 0.5 g (1 tsp) dill together caused this inhibition, probably due to their combined furanocoumarin content. On the other hand, fresh Allium spp. vegetables (100 g leeks, 75 g onions, 10 g chives, plus 5 g garlic) did not alter caffeine metabolism.15
Fresh vegetable juices taken as nutritional supplements for their antioxidant content frequently include plants from the cabbage or carrot families. These juices can result in consumption of phytonutrient amounts unlikely to be attained through normal diet. In such cases, as in citrus juices and their impact on transported proteins and/or CYP 3A4, significant interactions may result.
Altered Absorption with Fruit Juices by CYP or Transporter Inhibition
The consumption of common beverages can also impact absorption by affecting drug metabolism in the intestinal mucosa. The most widely recognized influence is the inhibition in the gut of the isozyme CYP 3A4 by grapefruit juice, thereby increasing bioavailability of the isozyme's drug substrates and increasing the risk of adverse effects. Interactions with grapefruit juice occur after a single exposure to an 8 oz glass of juice (about 250 mL). Large and clinically significant interactions have been shown with grapefruit juice and the statins lovastatin and simvastatin, the antihistamine terfenadine, and the antiarrhythmic amiodarone; combining these drugs with grapefruit juice should be avoided. Several dozen additional moderate or weak interactions have been identified with a variety of drugs.18
Avoidance of grapefruit juice is recommended for the statins (atorvastatin) and calcium-channel antagonists (amlodipine, felodipine, nifedipine, nimodipine). Others that should be monitored for side effects include HIV protease inhibitors, sedatives, anxiolytic and other psychotropic agents, oral contraceptives, and corticosteroids. Still others are not clinically significant and require no special attention.19 Complete recovery from the isozyme inhibition is expected within 72 hours.18,20
Transport proteins are also affected by common fruit juices. The organic anion transporting polypeptide facilitates drug uptake at the intestinal level. Grapefruit, orange, and apple juices have been shown to inhibit this mediator in humans when 1.2 L were consumed over three hours, thereby reducing absorption of fexofenadine from the gut.21 The inhibition of fexofenadine transport by OATP1A2 with 300 mL of grapefruit juice was shown to be clinically pertinent.22
Influence of Citrus Juices and St. John's Wort Products on P-glycoprotein Substrates
A much more familiar transporter protein is P-glycoprotein (Pgp). Its activity in human intestinal mucosal cells is a major factor in reducing the absorption of some drugs. Pgp is a cell membrane transport protein that pumps certain hydrophobic substrates, including some carcinogens, out of cells (efflux) and back into the intestinal lumen. Inducing its activity or increasing its content in enterocytes reduces absorption of drugs effluxed by Pgp. The inhibition of Pgp enhances the retention of drugs that would otherwise be expelled from cells by this transporter system. Drugs are not only substrates of Pgp, but many also act as its inducers or inhibitors.23
Citrus juices also have Pgp-modulating capabilities. Substantial reductions in the oral absorption of the Pgp substrates ivermectin and celiprolol have been demonstrated for orange juice, following consumption of 750 mL over four hours, or 200 mg three times daily for 2.3 days. However, the mechanism for these interactions has not been determined definitively.24,25 The modest changes in Pgp activity by grapefruit juice on digoxin absorption is not considered important.26,27
St. John's wort (Hypericum perforatum) is recognized as a botanical inducer of CYP 3A4. Digoxin is a substrate of Pgp but not CYP.28 The St. John's wort extract LI160 given to 25 healthy volunteers at the standard dose of 900 mg daily did not affect stable digoxin levels after one day, but after 10 days reduced the peak concentration 26%, the 24-hour post-dosing concentration by 33%, and the 24-hour area under curve (AUC) by 25%. These results indicate reduced absorption through induction of Pgp.29
Different St. John's wort dosages and formulations used with digoxin for 14 days vary in their influence on its bioavailability in humans. While 900 mg daily of the extract LI160 reduced digoxin AUC by 25% compared to placebo, 4 g daily of encapsulated herb powder reduced digoxin AUC by 27%, and 2 g of powdered herb capsules decreased AUC by 18%. Hyperforin daily dosage was similar between the extract (29 mg) and 4 g of powder (21 mg). Using daily either 0.5 g of the same powdered herb capsules, 2 g of a different powdered St. John's wort, 2 cups of the tea each made with 1.75 g herb, 1.2 g of an encapsulated oil extract, 20 mL fresh juice, or 500 mg of a 5:1 strength 50% ethanolic extract ZE117 caused no significant change in AUC or trough levels when compared to placebo. All of these preparations provided low hyperforin doses (< 3.6 mg). Whereas hyperforin dosage correlated well with Pgp induction, hypericin and flavonoid dosage did not.30 In a separate study, 240 mg extract delivering 3.5 mg hyperforin daily for 10 days in 28 volunteers was inadequate to significantly reduce digoxin absorption.31
Pgp effects of other herb preparations are not documented in humans. Though milk thistle silymarin extract inhibits Pgp in vitro,32 when tested with the Pgp substrate digoxin in 16 healthy humans, 900 mg milk thistle extract (440 mg silymarin) daily for 14 days did not significantly alter the drug bioavailability.33 There was actually a tendency toward reducing digoxin levels, suggesting potential Pgp induction. Black cohosh extract at 40 mg daily had no Pgp effect,33 though it had also been an inhibitor in vitro.34 Similarly, 240 mg daily of a ginkgo product did not alter digoxin pharmacokinetics in eight healthy subjects.35
Problems with CYP Isozyme Research for Botanicals
In making assessments of pharmacokinetic interactions, it is important to base judgments on data obtained from human studies with herbs or their extracts, since the expression of the CYP isozymes varies widely within the animal kingdom. Many human CYP 3A4 substrates are not metabolized by rat CYP3A, so rats are not appropriate models for humans. Also, rabbits have different CYP isozymes for one-third of drugs tested. Pigs, minipigs, and monkeys show similar results to humans but are comparatively expensive animals to maintain and study in relatively large numbers.36 Even among humans, genetic polymorphism can produce variations in drug metabolism for substrates of CYP 2B6 (3-4% Caucasians), 2C9 (1-3% Caucasians), 2C19 (3-5% Caucasians; 15-20% Asians), and 2D6 (5-10% Caucasians).5
Effects of isolated components cannot be assumed to represent the activity of phytochemically complex plants or their products. For example, isothiocyanates from cruciferous vegetables are CYP 1A1 and 2B1 inhibitors in vitro and in animals,37,38 whereas the whole vegetables39,40 and their indole metabolites38,41 are inducers. In vitro and in vivo results often do not correlate. Indole-3-carbinol, an enzymatic derivative from cruciferous vegetables, inhibits CYP conversion of estradiol at the 2-carbon in vitro,42 but induces the detoxifying CYP 2-hydroxylation of estradiol in rats and humans.42,43
FDA guidelines encourage routine in vitro evaluation of CYP metabolism and influence for all new drugs. Most CYP botanical studies are in vitro, though this unvalidated testing is proving unreliable. CYP assays rely on enzyme proteins, but these can be readily precipitated and inactivated by tannins commonly found in herbs.12 Also, reduction of heme (organic iron) from the ferric (Fe3+) to ferrous (Fe2+) enzyme is necessary for isozyme catalytic activity. Compounds that form complexes with the heme iron lead to CYP inhibition.44 As indicated previously, phenolic compounds in many botanicals apparently bind to ferric ion in solution.13 In another example, E. purpurea root extracts with phenolic caffeoyl conjugates can both chelate metals (e.g., copper) and block ferrous-ferric oxidation-reduction biological reactions in vitro.45,46 Tincture of E. purpurea root is a strong CYP 3A4 inhibitor in vitro,47 but the root solid extract at 1.6 g/d for eight days did not alter midazolam clearance when the drug was given orally to 12 human subjects and induced metabolism of intravenous midazolam.48
Inhibition of CYP 3A4 by licorice extract and its isoflavan component glabridin in vitro was associated with loss of the intact heme moiety.49 Though licorice extract was found to be a CYP 3A4 inhibitor in vitro,47,49 the extract and glycyrrhizin were 3A4 inducers when given orally to mice.50,51 In contrast, a 1 g dose of a freeze-dried water extract given twice daily to 10 human subjects for seven days in a randomized, placebo-controlled double-blind crossover study had no effect on the pharmacokinetics of the 3A4 substrate midazolam.52
By precipitating protein and binding iron, botanical extracts with polyphenols can produce isozyme inhibition in vitro, even though they are inducers in vivo. Many such components apparently interfere with in vitro inhibition studies. For example, in one study using water extracts (tannins are water-soluble), for all tested isozymes (CYP 2C9, 2C19, 2D6, and 3A4) there was > 75% inhibition with all five types of black tea that are high in tannin. In addition, results for all four isozymes showed > 50% inhibition for cloves, ginger, oregano, sage, thyme, turmeric, chamomile, feverfew, goldenseal, and St. John's wort, and > 25% inhibition for gotu kola and eleuthero. Most of these isozyme inhibitions were in the > 90% range. Even the strong CYP 3A4 inducer St. John's wort was a CYP 3A4 inhibitor in this in vitro study.53
Other herbs or their extracts have been strong inhibitors of CYP 3A4 in vitro, but in human studies have shown no significant effects. Though soy extract with 100 mg isoflavones daily for 14 days produced no effect on metabolism of CYP 3A4 substrate cortisol in humans, unhydrolyzed soy extract tended to induce 3A4 in vitro, but hydrolyzed soy extract strongly inhibited 3A4 in vitro.54 Kava root extracts are in vitro inhibitors of CYP 3A4,55-57 but in one study an extract induced production of 3A4 mRNA in vitro, mediated by pregnane X receptor (PXR).58 Strong kavapyrone CYP3A activators dihydromethysticin and desmethoxyyangonin only slightly activated PXR in vitro, suggesting an indirect or independent mechanism.59 Yet a human study using 1 g root extract twice daily for 28 days found neither inhibition nor induction of midazolam CYP 3A4 metabolism in 12 men and women.60
There are significant problems even in human studies. For some drugs the relationship between concentration and activity is not linear. For example, with certain drugs like midazolam a change of less than 50% is considered weak. Altering metabolism of one isozyme does not necessarily result in altered clinical effects, since some drugs are substrates for multiple isozymes.36 Even for the best studied herbal extract in regard to drug interactions, standardized St. John's wort extract, most clinical trials have been small, nonrandomized, uncontrolled, use variable methodology for dosage and duration, and provide inadequate product characterization. This makes many isolated study results relatively inconclusive, though consistent trends among studies are supportive. Higher quality research is necessary to achieve definitive findings.61 Still, these human studies provide the best data available thus far for evaluating the influence of CYP450 metabolism. Many will be examined and compared in the next segment of this series.
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