Drug Interactions with St. John’s Wort
Drug Interactions with St. John’s Wort
By Jerry Cott, PhD
A large body of literature has become available on the interaction potential of St. John’s Wort (SJW, Hypericum perforatum); familiarity with the mechanisms underlying these interactions can help clinicians avoid potential problems.
CYP450 and P-glycoprotein
The cytochrome P450 (CYP450) enzymes are a family of biotransformative enzymes concentrated in the liver and intestinal mucosa, but also are found in the kidneys, skin, lungs, and other tissues. Many foods and drugs induce or inhibit (or both) the activity of CYP450 enzymes. Induction, because it depends on the rate of synthesis of new enzyme, is a slow process. Although usually noticeable after a few days, maximal induction effects may take two weeks. Inhibition is more rapid, and can become maximal within 24 hours of exposure to the inhibitor; likewise, inhibition may reverse more rapidly.
The most important CYP450 isoenzymes are CYP 2C, 2D6, and 3A4.1,2 CYP3A4, the most abundant hepatic enzyme, oxidizes more than half of all medications subject to oxidative metabolism.
In vitro assays are commonly used to screen for potential drug interactions, but they have considerable limitations. For instance, in vitro drug and enzyme concentrations must approximate those attained in vivo, since enzyme specificity may be lost at elevated concentrations. False positives may be generated when crude extracts are incubated directly with hepatocytes (often at thousands of times the physiological plasma level). The incubates often contain constituents that would never be absorbed if orally ingested. Thus, whole animal or human clinical studies are by far the most useful measure of metabolic alterations since they incorporate absorption effects, as well as the effects of stomach acids, digestive enzymes, and transport systems.
P-glycoprotein (Pgp) is an ATP-dependent pump that moves substrates out of cells. An inducible membrane transport protein, Pgp is found in normal human renal, intestinal, and biliary epithelia, adrenals, testis, and pregnant uterus, where it is a barrier to xenobiotic accumulation and a determinant of oral bioavailability of many drugs.3 It also is found in both the choroid plexus and cerebral endothelium and is an element of the blood-brain barrier.4
Pgp was initially discovered by cancer researchers studying multi-drug resistance that resulted in cross- tolerance or cross-resistance to structurally unrelated compounds due to an overexpression of a family of transporter proteins.5
In Vitro and In Vivo Studies
Crude SJW methanolic extracts inhibited CYP 1A2, 2C9, 2C19, 2D6, and 3A4 at very high concentrations; IC50 (concentration required to inhibit enzyme activity by 50%) values ranged from 10 to 1000 mcg/mL.6 The flavonoid compound I3,II8-biapigenin inhibited CYP 3A4, 2C9, and 1A2 activities with IC50 values of 0.08, 4.0, and 3.7 mcM, respectively.
Hyperforin, previously believed to be one of the active antidepressant compounds in SJW, is the primary constituent responsible for enzyme and transport protein induction. Hyperforin inhibited CYP 2D6, 2D9, and 3A4 with IC50 values of 1.6, 4.4, and 2.3 mcM, respectively. The significance of these data is uncertain since the concentrations were higher than those attained clinically, e.g., hyperforin maximum plasma level was reported to be 280 nM (150 ng/mL).7 Also, isolated chemical constituents may not be relevant to whole or crude plant extracts. However, within physiologically relevant concentrations, hyperforin induces CYP3A4 in hepatocyte cells via the pregnane X nuclear receptor (Ki= 27 nM)8 and the steroid X receptor.9
Hyperforin is not necessary for a therapeutic effect (a low hyperforin formulation, Ze 117, has shown efficacy in major depression).10 Clinical pharmacokinetic studies have shown this formulation lacks interaction potential with either the CYP3A4 system or the Pgp transporter.11
Rats given 300 mg/kg/d SJW extract orally for 10 days showed no changes in CYP450 liver enzyme activity.12 However, rats treated orally with SJW did show reduced plasma levels of warfarin.12 Together, these data suggest (in rats at least) that the metabolic induction by SJW occurs in the intestine, rather than in the liver.
Clinical Data: CYP Isoenzymes and Pgp
Studies appear to show no effect of three days or less of SJW administration on any CYP isoenzymes.13,14 There is a tendency towards induction of CYP3A4 at eight days15 and consistent induction of CYP3A4 at 14 days.14,16 Other CYP enzymes are not affected by SJW: Studies found no effect of SJW on CYP1A2 at eight days15 or 14 days;14 no effect on CYP2D6 at three days,13 eight days,15 or 14 days;14 and no effect on CYP2C9 at 14 days.14
SJW recently has been reported to induce Pgp as well as CYP3A4. Administering SJW extract for 14 days increased intestinal Pgp expression 3.8-fold in rats and 1.4-fold in humans.17 In another study, healthy volunteers were randomized to placebo or SJW 600 mg tid for 16 days. Pgp expression increased 4.2-fold from baseline in subjects treated with SJW (P < 0.05).18
Cyclosporine
Two cardiac graft rejections were recently reported.19 Both were men in their 60s receiving azothiaprine, cyclosporine, and corticosteroids, and were hospital- ized due to early signs of rejection three weeks after beginning standardized SJW (300 mg tid). Discontinu-ing SJW increased cyclosporine levels; both patients recovered.19
A 29-year-old woman who received a cadaveric kidney and pancreas transplant began taking SJW supplements for 4-8 weeks. Her previously stable cyclosporine concentrations became subtherapeutic; this was associated with organ rejection.20 Four weeks after stopping SJW, cyclosporine concentrations again became therapeutic. Reduced cyclosporin levels (without transplant rejection) associated with SJW have been reported in four publications, including single case reports,21,22 two cases,23 and a case series of 30 patients at one institution in Germany.24
Although oral bioavailability variation of cyclosporine was previously ascribed to CYP3A4 variability, it is now known that Pgp variably reduces the rate of intestinal absorption.25 Thus, SJW extracts may have reduced oral bioavailability of cyclosporin by inducing Pgp as well as CYP3A4.17,18 The potential SJW interaction with cyclosporine is marked, and coadministration of the two agents should be avoided.
Digoxin
SJW interacts with digoxin, a known substrate of Pgp transport that is not metabolized by P450 enzymes. Twenty-five healthy volunteers brought to steady-state digoxin levels continued to receive digoxin (0.25 mg/d) either with placebo or with 900 mg/d SJW (LI 160) for 10 days.26 The first dose of SJW extract had no effect, but 10 days of SJW treatment decreased digoxin area under the curve (AUC) 25% (P = 0.0035), reduced trough concentrations 33% (P = 0.0023), and reduced Cmax (maximum concentration) 26% (P = 0.0095). Administering SJW extract to eight healthy males over 14 days decreased digoxin 18% after a single dose of 0.5 mg.17
Protease Inhibitors
In healthy, HIV-negative subjects, steady-state kinetic parameters for indinavir were established and then compared to parameters after administering standardized SJW extract 300 mg tid for 14 days.27 Indinavir AUC decreased by 57% after the SJW therapy. Indinavir is a substrate of CYP3A4 and Pgp.28
Anticoagulants
A crossover study examined the effect of SJW (LI160) on phenprocoumon (an anticoagulant closely related to warfarin).29 Ten men received SJW (300 mg tid) or placebo; on day 11, each received a single dose of phenprocoumon (12 mg). SJW significantly decreased free phenprocoumon AUC (~17%; P = 0.007) compared with placebo.
Seven cases of patients stabilized on warfarin experiencing reduced INRs associated with SJW have been reported.30 No thromboembolic complications were noted. Warfarin is metabolized by CYP2C9; however, induction of Pgp also may play a role. In support of this possibility, rats treated with SJW showed no changes in liver enzyme activity, but did show reduced plasma levels of orally administered warfarin.12
Oral Contraceptives
Two unintended pregnancies associated with the use of SJW occurred in long-term oral contraceptive users. Both had successfully used oral contraceptives for more than eight years and both became pregnant within five months of starting SJW (see Alternative Therapies in Women’s Health, April 2002). Breakthrough bleeding also has been reported.30,31 Steroids are known substrates of CYP3A4.
Theophylline
Theophylline has been reported to be metabolized (by demethylation) to a significant degree by CYP1A2.32,33 CYP1A2 enzymes are induced by tobacco, charbroiled meat, cruciferous vegetables, and a high-protein diet. Treatment with SJW for eight days in 16 subjects showed no effects on CYP1A2,34 and no in vivo data suggest an interaction of SJW with CYP1A2.
A single report of a possible theophylline-SJW interaction is probably a spurious association. A 42-year-old woman who smoked half a pack of cigarettes daily and took 11 other prescription medications (most of which affect CYP enzymes) took SJW for two months and was found to have subtherapeutic theophylline levels, which rose within seven days of discontinuing SJW.35 This report also discussed unpublished in vitro data suggesting induction of CYP1A2 with pure hypericin at concentrations several hundred times greater than those found in plasma. This report is difficult to evaluate and does not constitute evidence for a SJW-theophylline interaction.
Carbamazepine
Eight healthy volunteers received carbamazepine 100 mg twice daily for three days, then 200 mg twice daily for three days, then 400 mg once daily for 14 days.36 Blood was drawn on day 14, then subjects took 300 mg SJW (0.3% hypericin) tid with meals and with carbamazepine (400 mg) for 14 days. On day 35, plasma samples were analyzed for carbamazepine and its metabolite carbamazepine-10,11-epoxide. SJW administration did not affect carbamazepine concentrations at peak, trough, or AUC, suggesting that SJW either is not a particularly powerful CYP3A4 inducer, or that it cannot induce carbamazepine metabolism beyond the extent to which carbamazepine induces itself.
Antidepressants
Although concern has been expressed about SJW’s ability to inhibit monoamine oxidase (MAO) in vitro, no clinical or animal reports of MAO inhibition exist. Current evidence suggests that MAO inhibition may be an in vitro artifact.37 There are a few case reports of serotonin syndrome associated with SJW in the United States (no such cases have been reported in Europe).38 A case series of four elders with mild serotonin syndrome associated with combining SJW with the serotonin reuptake inhibitor sertraline or the atypical antidepressant nefazodone (one case) were consistent with exaggerated side effects of sertraline, namely, nausea, vomiting, and restlessness.39 All patients were stable on medication and experienced these effects within 3-4 days of adding SJW.
Literature references to drug metabolism and sertraline are conflicting. Most references do not list sertraline as a substrate of CYP3A4,40 but in one case, a 12-year-old boy experienced a serotonin syndrome when eryth-romycin, a known CYP3A4 inhibitor, was added to sertraline.41
A mild inhibiting action of SJW on CYP3A4 (demonstrated in acute dosing studies) could have increased sertraline or nefazodone plasma levels; an exaggerated serotonergic response consistent with increased nefazodone levels has been linked to acute inhibition of CYP3A4.42 The opposite effect could be predicted if SJW administration preceded the antidepressant.
This is in fact the result of a clinical trial of amitriptyline and SJW in which 12 depressed patients received 900 mg SJW extract with 75 mg twice daily of amitriptyline for 14 days.43 AUC decreased 21.7% for amitriptyline and 40.6% for nortriptyline. Levels of amitriptyline and its metabolite continuously decreased over the 14-day period, consistent with enzyme induction.
Amitriptyline is another drug for which consider- able contradiction exists in the literature regarding its metabolism. David Flockhart’s comprehensive drug interaction table (http://medicine.iupui.edu/flockhart/) lists amitriptyline as a substrate for CYP 1A2, 2C19, 2C9, and 2D6, while Feucht and Weissman also list it as a substrate for CYP3A4 and glucuronyl transferase.42
Conclusion
SJW reduces plasma levels of indinavir, cyclosporine, digoxin, and anticoagulants. Pregnancies have been reported in long-term oral contraceptive users after initiation of SJW. Repeated dosing of SJW (8-14 days) induces intestinal CYP3A4 activity. Chronic administration of SJW also induces the drug transporter protein, Pgp. The few drugs that are substrates of both systems (e.g., indinavir and cylcosporine) are doubly affected by SJW. Hyperforin appears to be responsible for both enzyme and Pgp induction, though it may not be necessary for therapeutic activity.
Dr. Cott is Scientific Director and Chief Science Officer at Scientific Herbal Products, Inc. in College Park, MD.
References
1. Hardman JG, et al, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 1996:11-14.
2. Caraco Y. Genetic determinants of drug responsiveness and drug interactions. Ther Drug Monit 1998;20:517-524.
3. Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther Drug Monit 2000;22:137-140.
4. Sugiyama Y, et al. Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: Importance in the drug delivery to the brain. J Control Release 1999;62:179-186.
5. Johnstone RW, et al. Multiple physiological functions for multidrug transporter P-glycoprotein? Trends Biochem Sci 2000;25:1-6.
6. Obach RS. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s Wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 2000;294:88-95.
7. Biber A, et al. Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Pharmacopsychiatry 1998;31(Suppl 1):36-43.
8. Moore LB, et al. St. John’s Wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000;97:7500-7502.
9. WentWorth JM, et al. St. John’s Wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol 2000; 166:R11-16.
10. Kaufeler R, et al. Efficacy and tolerability of Ze 117 St. John’s Wort extract in comparison with placebo, imipramine and fluoxetine for the treatment of mild to moderate depression according to ICD-10. An overview. Pharmacopsychiatry 2001;34(Suppl 1):S49-S50.
11. Brattström A. St. John’s Wort extract Ze 117: Efficacy and safety. Deutsche Apotheker Zeitung (in press).
12. Nöldner M, Chatterjee S. Effects of two different extracts of St. John’s Wort and some of their constituents on cytochrome P450 activities in rat liver microsomes. Pharmacopsychiatry 2001;34(Suppl 1):S108-110.
13. Markowitz JS, et al. Effect of St. John’s Wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci 2000;66:133-139.
14. Wang Z, et al. The effects of St. John’s Wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001;70:317-326.
15. Ereshefsky B, et al. Determination of SJW differential metabolism at CYP2D6 and CYP3A4 using dextromethorphan probe technology. Abstracts from the 39th Annual Meeting, New Clinical Drug Evaluation Unit. Boca Raton. FL; June 1999.
16. Roby CA, et al. St. John’s Wort: Effect on CYP3A4 activity. Clin Pharmacol Ther 2000;67:451-457.
17. Dürr D, et al. St. John’s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000;68:598-604.
18. Hennessy M, et al. St. Johns Wort increases expression of P-glycoprotein: Implications for drug interactions. Br J Clin Pharmacol 2002;53:75-82.
19. Ruschitzka F, et al. Acute heart transplant rejection due to St. John’s Wort. Lancet 2000;355:548-549.
20. Barone GW, et al. Drug interaction between St. John’s Wort and cyclosporine. Ann Pharmacother 2000;34:1013-1016.
21. Mai I, et al. Hazardous pharmacokinetic interaction of St. John’s Wort (Hypericum perforatum) with the immunosuppressant cyclosporin. Int J Clin Pharmacol Ther 2000;38: 500-502.
22. Moschella C, Jaber BL. Interaction between cyclosporine and Hypericum perforatum (St. John’s Wort) after organ transplantation. Am J Kidney Dis 2001;38:1105-1107.
23. Turton-Weeks SM, et al. St. John’s Wort: A hidden risk for transplant patients. Prog Transplant 2001;11:116-120.
24. Breidenbach T, et al. Profound drop of cyclosporin A whole blood trough levels caused by St. John’s Wort (Hypericum perforatum). Transplantation 2000;27;69:2229-2230.
25. Lown KS, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 1997;62:248-260.
26. Johne A, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s Wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338-345.
27. Piscitelli SC, et al. Indinavir concentrations and St. John’s Wort. Lancet 2000;355:547-548.
28. Choo EF, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000; 28:655-660.
29. Maurer A, et al. Interaction of St. John’s Wort extract with phenprocoumon. Eur J Clin Pharmacol 1999;55:A22.
30. Yue QY, et al. Safety of St. John’s Wort (Hypericum perforatum). Lancet 2000;355:576-577.
31. Ratz AE, et al. St. John’s Wort: A pharmaceutical with potentially dangerous interactions [in German]. Schweiz Rundsch Med Prax 2001;90:843-849.
32. Ha HR, et al. Metabolism of theophylline by cDNA-expressed human cytochromes P-450. Br J Clin Pharmacol 1995;39:321-326.
33. Lee H, et al. Structure-related inhibition of human hepatic caffeine N3-demethylation by naturally occurring flavonoids. Biochem Pharmacol 1998;55:1369-1375.
34. Gewertz N, et al. Determination of differential effects of St. John’s Wort on the CYP1A2 and NAT2 metabolic pathways using caffeine probe technology. Abstracts from the 39th Annual Meeting, New Clinical Drug Evaluation Unit. Boca Raton. FL; June 1999.
35. Nebel A, et al. Potential metabolic interaction between St. John’s Wort and theophylline. Ann Pharmacother 1999; 33:502.
36. Burstein AH, et al. Lack of effect of St John’s Wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000;68:605-612.
37. Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry 1997; 30(Suppl. 2):108-112.
38. Schulz V. Incidence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomedicine 2001;8:152-160.
39. Lantz MS, et al. St. John’s Wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10.
40. Xu ZH, et al. Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes. Br J Clin Pharmacol 1999;48: 416-423.
41. Lee DO, Lee CD. Serotonin syndrome in a child associated with erythromycin and sertraline. Pharmacotherapy 1999;19:894-896.
42. Feucht CL, Weissman SB. Psychiatric and antiretroviral agents: Associated drug interactions. TEN 2000;2:69-73.
43. Roots I, et al. Interaction of a herbal extract from St. John’s Wort with amitriptyline and its metabolites. Clin Pharm Ther 2000;67:159.
Cott J. Drug interactions with St. John's wort. Altern Ther Women's Health 2002;4:60-64.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.