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Drug Pharmacokinetic Interactions Following Consumption of Plant Products
Part 2 of a series on herb-drug interactions
By Francis Brinker, ND Dr. Brinker is Clinical Assistant Professor, Department of Medicine, College of Medicine, at the University of Arizona; he is a retained consultant for Eclectic Institute, Inc.
Conflicting Results in Human Studies with CYP3A4 Drug Substrates
In vitro isozyme inhibition results can yield false positives, giving rise to concerns over botanical influence on drug metabolism. Because more than 50% of medications are metabolized by CYP 3A4, the effects of herb preparations on this isozyme are particularly important. Unfortunately, not even all human research findings are consistent.1 (See Table 1.)
Garlic (Allium sativum) products' impact on CYP 3A4 substrates is not predictable. Ten healthy subjects taking two garlic caplets daily for three weeks reduced the plasma content of HIV protease inhibitor and CYP 3A4 substrate saquinavir by 50%. After 10 days, plasma levels were 35% less than baseline.2 However, 1.8 g of a standardized garlic extract daily for 14 days in 14 healthy subjects did not alter metabolism of 3A4 substrate alprazolam.3 Furthermore, garlic oil did not affect midazolam's metabolism by 3A4.4 (See Table 2.)
In the case of Asian ginseng (Panax ginseng), 200 mg/d for 14 days of an extract standardized to 4% ginsenosides failed to alter this isozyme's metabolism of cortisol in 20 humans,5 and daily doses for 28 days of 1.5 g extract standardized to 5% ginsenosides did not change the metabolism of CYP 3A4 substrate midazolam.4 However, 200 mg/d of uncharacterized ginseng for 18 days inhibited metabolism by CYP 3A4 of nifedipine, as indicated by increased peak plasma concentrations of 29%.6 In vitro tests found that ginsenoside Rd was a weak inhibitor of CYP 3A4, but Rf increased the activity of this isozyme at 3-4 times the concentration of Rd inhibition.7
In two separate studies, milk thistle extract was given to 10 human subjects (153 mg or 173 mg silymarin three times daily for two or three weeks, respectively) and did not inhibit CYP 3A4 metabolism of the substrate indinavir.8,9 Also, 175 mg milk thistle extract (80% silymarin) twice daily failed to alter bioavailability of midazolam in 12 humans after four weeks.10 While metabolism of erythromycin by CYP 3A4 was not significantly inhibited by the major component silybin, 3A4 oxidation of denitronifedipine was clearly inhibited in a mostly non-competitive fashion in vitro.11 The inhibition of CYP 3A4 by silybin, silydianin, and silycristin was shown in vitro to be dose-dependent but not therapeutically relevant due to the concentrations required.12,13 However, 140 mg/d silymarin did reduce bioavailability after nine days of Pgp/CYP 3A4 substrate metronidazole, either by inducing Pgp or 3A4.14 Silybin failed to reduce uptake of Pgp substrate ritonavir in vitro (as did hyperforin, paradoxically),15 but as noted previously, in 16 healthy humans 440 mg silymarin daily for 14 days produced a tendency toward reducing digoxin levels, suggesting potential Pgp induction.16 The combination of weak inhibition of both Pgp and 3A4 may be responsible.
In the another example, goldenseal tincture and its herb tea were the strongest CYP 3A4 inhibitors tested in vitro of 21 herb extracts and 20 herb and black teas.17,18 This was believed to be largely due to berberine,19 generally considered its primary active component.20 For one extract, inhibition in vitro is due primarily to the alkaloid hydrastine, rather than berberine, that forms a stable adduct with the CYP 3A4 heme iron.19 In vivo 2.7 g daily for 28 days of goldenseal root extract inhibited midazolam 3A4 metabolism by 40% in 12 men and women.21 However, 2.28 g of the root given daily to 10 healthy volunteers for 14 days failed to affect the pharmacokinetics of CYP 3A4 substrate indinavir.22
Effects can differ depending on the plant part, its relative component make-up, and the absorption of its active compounds. Echinacea purpurea root solid extract at 1.6 g/d for eight days increased the clearance and reduced bioavailability of IV midazolam but did not alter its clearance when the drug was given orally to 12 human subjects. These results suggest that some root compounds inhibit intestinal CYP 3A while others induce liver CYP 3A.23 When an E. purpurea whole plant extract was given in a 1.6 g daily dose to 12 healthy human subjects for 28 days, no significant effect on oral midazolam was detected.10 E. purpurea root tincture is a strong CYP 3A4 inhibitor in vitro, more so than a tincture of its tops.17 While the tops and root have similar concentrations of the main caffeic acid derivative cichoric acid, the roots contain much greater concentrations of alkamides.24 The alkamides are systemically available after oral consumption by humans, whereas caffeic acid conjugates are not.25 These differences in phytochemical content and bioavailability may be reflected in enteric versus hepatic CYP influence.
St. John's Wort Products as Prototypical Inducers of CYP 3A4?
St. John's wort extract LI160 given at 900 mg daily for 14 days increased duodenal P-glycoprotein 1.4-fold, duodenal CYP 3A4 1.5-fold, and hepatic 3A4 1.4-fold in humans.26 The dual effect on CYP 3A4 and Pgp increases the impact on drugs that are substrates of both. Extract LI160 at 900 mg daily for two weeks prior to administering single doses of simvastatin and pravastatin to eight healthy males each resulted in lower plasma levels of simvastatin and its active metabolite, but pravastatin plasma concentration was not influenced. Simvastatin is a substrate of P-glycoprotein and CYP 3A4 in the intestinal wall and liver, but pravastatin is not a substrate for either.27
St. John's wort standardized extract at 900 mg/d given for 14-47 days to four patients on methadone resulted in a 19%-60% (median 47%) decrease in methadone plasma concentration to dose ratios. Methadone is also a substrate of P-glycoprotein and CYP 3A4. Two patients reported opioid withdrawal-like symptoms.28 The P-glycoprotein and CYP 3A4 substrates indinavir and cyclosporin have their bioavailability significantly reduced in human studies. Several case reports have also been published indicating their reduced efficacy, leading to increased HIV viral load and organ (heart, kidney, liver, pancreas) rejection, respectively, when used with St. John's wort extract.29 Drugs that are purely CYP 3A4 substrates and have reduced bioavailability in humans taking St. John's wort extract include alprazolam, imatinib, midazolam, nifedipine,6 omeprazole,30 oral contraceptives, quazepam, tacrolimus, and verapamil.29,31
Studies extended beyond 10 days are necessary to detect effects of induction on Pgp and CYP proteins. For example, the standard research CYP 3A4 drug substrate alprazolam showed increased clearance and decreased bioavailability when 900 mg daily St. John's wort extract LI160 was given for 14 days prior and concurrently to 12 healthy subjects.32 In an earlier study by the same research group, seven healthy subjects given 900 mg daily for only four days of an extract standardized to 0.3% hypericin did not show significant changes in pharmacokinetic parameters for alprazolam.33 When interaction with alprazolam was studied in the context of daily hyperforin dose, it was found in 28 volunteers that 240 mg extract providing 3.5 mg hyperforin daily for 10 days was insufficient to increase alprazolam metabolism,34 whereas 900 mg of an extract for 28 days that delivered 4.8 mg hyperforin per day induced midazolam metabolism by 141%, when measured as a single timepoint phenotypic metabolic ratio.35
Hyperforin Key Pgp and CYP 3A4 Inducer
Like other misleading in vitro findings, St. John's wort tincture was one of the most potent herbal tinctures tested in vitro for inhibiting CYP 3A4.17 However, induction studies correlate with the human effect of the extract and component hyperforin. St. John's wort extracts and hyperforin have been shown to markedly induce CYP 3A4 expression in primary human hepatocytes in vitro. Hyperforin is the extract component that acts as a potent ligand for activating the steroid X receptor (pregnane X receptor) in vitro that in turn regulates expression of CYP 3A4.36 St. John's wort and its hyperforin also induce Pgp in humans.37
In a crossover study with 10 renal transplant patients using cyclosporine, one group received 900 mg/d for 14 days of an extract with 4.7% hyperforin content and the other group received an extract with less than 0.1% hyperforin. The high hyperforin extract led to significantly less cyclosporine bioavailability, peak concentration and plasma concentration at the end of 12 days requiring an increased daily dose, whereas the low hyperforin caused no changes in cyclosporine parameters. Cyclosporine is a substrate for both Pgp and CYP 3A4.38
It appears that St. John's wort with low-hyperforin content is safe, but is it effective? A randomized, double-blind, placebo-controlled multi-clinic trial compared 900 mg daily of extracts containing 0.5% (WS 5573) and 5% (WS 5572) hyperforin that were otherwise identical. These were used in treating 147 patients with mild-to-moderate depression (initial Hamilton Depression Rating Scale [HAMD] average > 20) for six weeks. The group receiving the 5% hyperforin extract had the largest reduction in the HAMD from the beginning of the study (-10.3), followed by WS 5573 (-8.5) and then the placebo (-7.9). Only the 5% hyperforin extract significantly improved the score in comparison with placebo.39 In another study it was determined that those who were more severely depressed (HAMD > 22) benefited even more from the 5% hyperforin extract, but not with the 0.5% hyperforin WS 5573.40 In contrast, ZE117 is a 5:1 strength 50% ethanolic extract low in hyperforin,37 and it has been effective in randomized, placebo-controlled, double-blind, multicenter clinical trials for depression,41 comparable to imipramine42 and fluoxetine.43,44
Other CYP450 Influences in Humans with Popular Botanical Preparations
In 16 subjects given 10 mL of aged garlic (Allium sativum) extract daily for 12 weeks, no effect on CYP 2E1 metabolism of acetaminophen was detected.45 The extract used minced garlic incubated in 15-20% alcohol for 8-12 months and had as its major constituent S-allyl-cyseine, but very little diallyl sulfide. Diallyl sulfone, a metabolite of the main aromatic garlic component diallyl sulfide, given in doses as low as 25 mg/kg prevented hepatotoxicity in mice from bioactivation of CYP 2E1 substrate acetaminophen.46 Aged garlic alcoholic extract does not prevent acetaminophen hepatotoxicity in vitro, though its component S-allyl-cysteine can reduce it.47 Non-aged garlic extracts consistently inhibit CYP 2E1 in vitro and in vivo.48-50 Consumption of 1,500 mg/d of garlic oil for 28 days in 12 healthy subjects inhibited chlorzoxazone metabolism by CYP 2E1 and enhanced sedation from the drug.4
When 1 g kava root extract was given twice daily for 28 days to 12 healthy volunteers, it inhibited metabolism of the CYP 2E1 substrate chlorzoxazone by 40%, though not substrates for CYP 1A2, 2D6, or 3A4.21 In another contrast between human and in vitro results, kava root preparations and its various isolated kavalactones have been shown to be in vitro inhibitors of CYP 1A2, 2C9, 2C19, 2D6, and 3A4 substrate metabolism,18,51-53 though 2E1 was unaffected.51
E. purpurea root extract at 1.6 g/d for eight days increased bioavailability of caffeine when the drug was given orally to 12 subjects, suggesting the root inhibits CYP 1A2.23 However, when an E. purpurea whole plant extract was given in a 1.6 g daily dose to 12 healthy subjects for 28 days, no significant effect on caffeine was detected.10 Again, this may reflect the greater alkamide content of the root54 and its systemic bioavailability.26
Ginkgo (Ginkgo biloba) leaf concentrated extract EGb761 at 280 mg/d in 12 Chinese subjects significantly decreased omeprazole bioavailability, likely inducing its metabolism by CYP 2C19, but also reducing urinary excretion of its major metabolite.55 This may be a consequence, as previously noted, of CYP 2C19 being subject to genetic polymorphism in 15-20% of Asians.56 So, depending on the specific isozyme makeup of the subpopulation studied, this result may not be typical of most responses.
Alterations in drug pharmacokinetics are a fact of life for everyone who takes medications. Inhibiting and inducing influences on drug absorption and metabolism commonly occur via the use of other drugs and consumption of common beverages and foods. Medicinal herbs are no exception in their potential to alter the bioavailability of certain medications. An important aspect in evaluating their influence is the understanding of the relative merit of different types of herb-drug interaction studies. Research done in vitro to screen a variety of plant preparations for CYP450 inhibition is suggestive at best, with numerous false-positive results documented. These misleading outcomes may be explained by exceedingly high concentrations of phytochemicals that are not achieved in vivo, polyphenolic binding and interference with CYP isozymes, and/or a disproportionate exposure to phytochemical mixtures that does not occur systemically due to variable botanical component pharmacokinetics. Animal studies have severe limitations for predicting human outcomes, due to distinct and unique species expression of CYP isozyme profiles.
Human studies likewise suffer limitations in what can be concluded about a particular herb. Varying outcomes with the same plant source can result from using different parts, preparations, doses, and durations. Isolated studies of a single preparation are therefore relatively inconclusive as regards different types of products from the same plant. The advantage of identifying and quantifying particular active phytochemicals in the different preparations is exemplified by hyperforin in St. John's wort products. The pertinent factor thus becomes the relative content and intake of the phytochemical, not the plant per se. Since botanical preparations may contain multiple phytochemicals with different drug metabolism influences, each type of preparation should be separately considered in terms of its own makeup, pharmacokinetics, and potential for influence. An over-simplistic approach for assessing or generalizing these influences is likely to be unreliable.
Where a well-designed human study demonstrates an interaction between a particular botanical preparation and a specific pharmaceutical, this combination should ordinarily be avoided unless it leads to an improved clinical outcome with little or no increased risk of adverse effects. If a single human study indicates no interaction with a particular drug, a similar combination may be cautiously employed. However, it cannot be assumed that all preparations from the same plant will necessarily yield the same result.
When human studies consistently demonstrate that the bioavailability of two or more substrates of the same transport protein or CYP450 isozyme is altered by prior or concurrent use of a particular botanical, combined use of these and other substrates of the same transporters and/or isozymes should not be used together with that botanical unless the modified clearance is taken into account by careful monitoring and dosage adjustments. Even in these cases, such combinations should only be considered when a relatively broad therapeutic index helps assure a safe and effective dosage for the specific drug involved. In cases where patients are consuming multiple medications, further risk of potential interactions by the introduction of pharmacologically active substances, whether pharmaceutical or botanical, should only be considered with great circumspection.
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28. Eich-Hochli D, et al. Methadone maintenance treatment and St. John's worta case report. Pharmacopsychiatry 2003;36:35-37.
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30. Wang LS, et al. St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther 2004;75:191-197.
31. Tannergren C, et al. St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism. Clin Pharmacol Ther 2004;75:298-309.
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