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St. John's wort and irinotecan-induced diarrhea

DOI:10.1016/j.taap.2006.12.019
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Timothy Birdsall at Pinnacle Dermatology
Timothy Birdsall
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Letter to the Editor
St. John's wort and irinotecan-induced diarrhea
Dear Sirs,
The article by Hu et al. (2006) on St. John's wort and
irinotecan-induced diarrhea ignores the well-known CYP450
and P-glycoprotein effects of St. John's wort on drug
metabolism. It is also troubling that the authors appear to
misrepresent the study by Mathijssen et al. (2002) when they
state: “Interestingly, a recent pilot study in 5 cancer patients
found that oral treatment of SJW at 900 mg/day for 18 days
alleviated irinotecan-induced diarrhea (Mathijssen et al., 2002).
However, the mechanism for this is unknown.”
Mathijssen et al. actually did NOT report less diarrhea
(although they did show a decrease in SN-38, the irinotecan
metabolite associated with diarrhea): “Clinically, irinotecan-
induced neutropenia, as measured by a decrease in the number of
circulating neutrophils, was the most prominent side effect, and
the spectrum of side effects was unchanged by SJW”. These
researchers did extensive pharmacokinetic studies, although the
small sample size (n= 5), limited statistical significance of some
of the data. They demonstrated that St. John's wort decreased
irinotecan area under the curve by 12% and peak irinotecan
plasma concentration by 20%. Plasma SN-38 area under the
curve was decreased 40% by St. John's wort, as was peak SN-38
plasma concentration. Mathijssen et al. conclude “Overall, our
findings suggest that irinotecan metabolism and toxicity are
altered by SJW and that the two agents cannot be given safely in
combination without compromising overall antitumor activity”.
St. John's wort has been shown to interfere with the metabolism
of numerous pharmaceuticals metabolized by CYP450 3A4,
including alprazolam (Markowitz et al., 2003), cyclosporine A
(Moschella and Jaber, 2001), digoxin (Mueller et al., 2004),
indinavir (Piscitelli et al., 2000), and simvastatin (Sugimoto et
al., 2001). Since irinotecan is known to be metabolized
extensively by CYP450 3A4, these pharmacokinetic considera-
tions should have been taken into account in the study design by
Hu et al., or at least mentioned in the discussion of their findings.
References
Hu, Z.P., Yang, X.X., Chan, S.Y., Xu, A.L., Duan, W., Zhu, Y.Z., Sheu, F.S.,
Boelsterli, U.A., Chan, E., Zhang, Q., Wang, J.C., Ee, P.L., Koh, H.L.,
Huang, M., Zhou, S.F., 2006. St. John's wort attenuates irinotecan-induced
diarrhea via down-regulation of intestinal pro-inflammatory cytokines and
inhibition of intestinal epithelial apoptosis. Toxicol. Appl. Pharmacol. 216,
225–237.
Markowitz, J.S., Donovan, J.L., DeVane, C.l., Taylor, R.M., Ruan, Y., Wang,
J.S., Chavin, K.d., 2003. Effect of St. John's Wort on drug metabolism by
induction of cytochrome P450 3A4 enzyme. JAMA 290, 1500–1504.
Mathijssen, R.H., Verweij, J., de Bruijn, P., Loos, W.J., Sparreboom, A., 2002.
Effects of St. John's wort on irinotecan metabolism. J. Natl. Cancer Inst. 94,
1247–1249.
Moschella, C., Jaber, B.L., 2001. Interaction between cyclosporine and Hy-
pericum perforatum (St. John's wort) after organ transplantation. Am. J.
Kidney Dis. 38, 1105–1107.
Mueller, S.C., Uehleke, B., Woehling, H., Petzsch, M., Majcher-Peszynska, J.,
Hehl, E.M., Sievers, H., Frank, B., Riethling, A.K., Drewelow, B., 2004.
Effect of St. John's wort dose and preparations on the pharmacokinetics of
digoxin. Clin. Pharmacol. Ther. 75, 546–557.
Piscitelli, S.C., Burstein, A.H., Chiatt, D., Alfaro, R.M., Falloon, J., 2000.
Indinavir concentrations and St. John's wort. Lancet 355, 547–548.
Sugimoto, K., Ohmori, M., Tsuruoka, S., Mishiki, K., Kawaguchi, A., Harada,
K., Arakawa, M., Sakamoto, K., Masada, M., Miyamori, I., Fujimura, A.,
2001. Different effects of St. John's wort on the pharmacokinetics of
simvastatin and pravastatin. Clin. Pharmacol. Ther. 70, 518–524.
Timothy C. Birdsall
Integrative Medicine, Cancer Treatment Centers of America,
Department of Naturopathic Medicine,
Midwestern Regional Medical Center,
2520 Elisha Avenue, Zion, IL 60099, USA
E-mail address: tim.birdsall@ctca-hope.com.
28 November 2006
Toxicology and Applied Pharmacology 220 (2007) 108
www.elsevier.com/locate/ytaap
0041-008X/$ - see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.taap.2006.12.019
... The authors suggested SJW might be further investigated for its potential to reduce the dose limiting intestinal toxicity of the drug. (51) This conclusion was subsequently criticized on the grounds that it ignored the "well known CYP450 and P-gp induction effects of SJW" and emphasized that SJW should not be coadministered with irinotecan due to the fact that the drug is "extensively metabolized by CYP450 3A4." (52) This criticism misses a most significant point for the herb literate practitioner: antiinflammatory herbs may help reduce chemotherapy induced intestinal side effects such as mucositis and diarrhea. Of course, SJW may not be the herb of choice for this indication, but in reality given the extensive publicity and understanding of the interaction potential of SJW with narrow therapeutic index anticancer drugs, most physicians, oncologists, educated patients, and all herb-literate non-conventional providers would avoid co-administration of SJW with these agents as a matter of routine. ...
... Ultimately a myriad of influences from the genetic to cultural concepts of health, and healing may also be sources of "interaction" with drugs, effectively constituting an "interactions universe", which can be represented in terms of a hierarchy of levels. (see Diagram 3 below) Diagram 3: The Interactions "Universe", reproduced with permission from Mosby from Stargrove, Treasure and McKee (52) A poignant aspect of negative attitudes towards herbal medicine is that botanicals contain valuable lessons and insights that hold the potential to transform present paradigms of conventional pharmacotherapeutics in a positive way. From contemporary drug development, which is inching away from the classical traditional "silver bullet" concept towards multi-target strategies "molecular multitasking" that is an inherent aspect of much natural compound activity, through to transdisciplinary therapeutic approaches incorporating botanicals that hold promise for improving therapeutic outcomes for cancer patients, the promise of medicinal plants significantly outweighs their perils. ...
Treading on the Tiger’s Tail: Interactions Between Herbs and Anticancer Drugs (2007)
Article
Full-text available
  • Jan 2007
... toll-like receptors (TLR)] and mucositis severity [57,107]. A number of interventions have also been studied in these models including St John's Wort [108][109][110][111], probiotic yeasts [112] and antioxidant agents targeting ROS production (e.g. fullerol) [53]. ...
Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets
Article
Purpose of review: Mucositis remains a prevalent, yet poorly managed side effect of anticancer therapies. Mucositis affecting both the oral cavity and gastrointestinal tract predispose to infection and require extensive supportive management, contributing to the growing economic burden associated with cancer care. Animal models remain a critical aspect of mucositis research, providing novel insights into its pathogenesis and revealing therapeutic targets. The current review aims to provide a comprehensive overview of the current animal models used in mucositis research. Recent findings: A wide variety of animal models of mucositis exist highlighting the highly heterogenous landscape of supportive oncology and the unique cytotoxic mechanisms of different anticancer agents. Golden Syrian hamsters remain the gold-standard species for investigation of oral mucositis induced by single dose and fractionated radiation as well as chemoradiation. There is no universally accepted gold-standard model for the study of gastrointestinal mucositis, with rats, mice, pigs and dogs all offering unique perspectives on its pathobiology. Summary: Animal models are a critical aspect of mucositis research, providing unprecedent insight into the pathobiology of mucositis. Introduction of tumour-bearing models, cyclic dosing scheduled, concomitant agents and genetically modified animals have been integral in refining our understanding of mucositis.
Progress in prevention and treatment of irinotecan-induced diarrhea
Article
  • Nov 2010
Molecular Mechanisms Underlying St. Johns Wort Drug Interactions
Article
The phytopharmaceutical agent St. John's wort (SJW) is currently under intense investigation. Studies of drug interactions resulting from concomitant use of SJW and conventional medication are of fundamental importance, since the use of SJW as a complementary and alternative medicine is highly popular. Intake of SJW often remains unrecognized by physicians resulting in clinical relevant alterations of treatment, as this phytopharmaceutical agent is available without prescription. This review elicits molecular explanations for clinical observations in terms of concomitant use of SJW and conventional drugs. Since patients suffering from severe diseases such as cancer are especially at risk, we focus on chemotherapeutic agents. There is strong evidence that SJW extract lowers drug plasma levels of various anti-cancer agents by pregnane X receptor activation resulting in induction of cytochrome P450 isotype 3A4, P glycoprotein and several other enzymes. New methods such as photophysical diagnosis (PPD) and photodynamic therapy (PDT) seem to be highly promising with respect to their clinical application. Due to its fluorescent activity and an intense accumulation in cancer cells, hypericin could be applied to locate tumorous tissues. Upon excitation by light, hypericin generates cytotoxic products rendering its use attractive as photosensitizing agent. In this review both PPD and PDT are explained in detail, with a particular focus on molecular mechanisms.
Effects of St. John’s Wort on irinotecan metabolism
Article
Full-text available
  • Sep 2002
St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7 micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.
Effect of St John's Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme
Article
Full-text available
St John's wort is a popular herbal product used to treat depression but it has been implicated in drug interactions. To assess the potential of St John's wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism. Open-label crossover study with fixed treatment order conducted March 2002 to February 2003 in a US general clinical research center involving 12 healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after 14 days of administration of St John's wort. Participants were given probe drugs (30 mg of dextromethorphan and 2 mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After a minimum 7-day washout period, participants began taking one 300-mg tablet 3 times per day. After 14 days of St John's wort administration, participants were given the probe drugs along with 1 St John's wort tablet to establish postadministration CYP activity; the St John's wort dosing regimen was continued for 48 hours. Changes in plasma pharmacokinetics of alprazolam as a probe for CYP 3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan, in urine as a probe for CYP 2D6 activity. A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St John's wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St John's wort administration (P =.26). A 14-day course of St John's wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications.
Effects of St. John's Wort on Irinotecan Metabolism
Article
St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m2, intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 μM × h (95% CI = 0.34 μM × h to 1.7 μM × h) versus 1.7 μM × h (95% CI = 0.83 μM × h to 2.6 μM × h) (P = .033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.
Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin
Article
  • Dec 2001
St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis
Article
Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1{beta}, IL-2, IL-6), interferon (IFN-{gamma}) and tumor necrosis factor-{alpha} (TNF-{alpha}) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1{beta}, IL-2, IL-6, IFN-{gamma} and TNF-{alpha} and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1{beta}, IFN-{gamma} and TNF-{alpha} was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-{alpha} mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.
Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin
Article
  • Dec 2001
Objective St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro-drug) and pravastatin were determined in this study.Methods Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double-blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24-hour period after the administration of each drug.ResultsRepeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P < .05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P < .05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half-life of simvastatin or pravastatin between the placebo and St John's Wort trials.Conclusions This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver.Clinical Pharmacology & Therapeutics (2001) 70, 518-524; doi: 10.1016/S0009-9236(01)64092-X
Idinavir concentrations and St John's Wort
Article
  • Mar 2000
St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-h indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.
Interaction between cyclosporine and Hypericum perforatum (St. John's Wort) after organ transplantation
Article
The use of herbal medicine has become increasingly popular in the United States. Hypericum perforatum (St. John's wort) is an herbal extract that is used widely as a folk remedy for depression. In this case report, we describe a kidney transplant recipient who developed marked reduction of cyclosporine therapeutic activity after the self-initiation of St. John's wort. Postulated mechanisms for the ability of this herbal extract to interact with pharmaceutical medications are presented, and the existing literature is reviewed.
Effect of St John's Wort Dose and Preparations on the Pharmacokinetics of Digoxin
Article
  • Jul 2004
St John's wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St John's wort formulations and doses with digoxin. A randomized, placebo-controlled, parallel-group study was performed in 96 healthy volunteers in 3 study parts. A 7-day loading phase with digoxin was followed by 14 days of comedication with placebo or one of 10 St John's wort products varying in dose and formulation. The pharmacokinetics of digoxin was determined before comedication and on day 14 of comedication. Comedication comprised traditionally used Hypericum products; 2 g powder without hyperforin, tea, juice, oil extract, and placebo had no significant interaction with digoxin nor did hyperforin-free extract (Ze 117) or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g). However, comedication with the high-dose hyperforin-rich extract LI 160 resulted in a reduction of digoxin area under the curve from time 0 to 24 hours (AUC(0-24)) of -24.8% (95% confidence interval [CI], -28.3 to -21.3), a reduction in digoxin maximal plasma concentration (C(max)) of -37% (95% CI, -42 to -32), and a reduction in digoxin plasma concentration at 24 hours after previous dosing (C(trough)) of -19% (95% CI, -27 to -11). Comedication with 4 g Hypericum powder with comparable hyperforin content resulted in a reduction in digoxin AUC(0-24) of -26.6% (95% CI, -37.3 to -15.9), a reduction in digoxin C(max) of -38% (95% CI, -48 to -18), and a reduction in digoxin C(trough) of -19% (95% CI, -27 to -10). Two grams of Hypericum powder with half the hyperforin content resulted in a less prominent reduction in AUC(0-24) of -17.7% (95% CI, -21.6 to -13.7), C(max) (-21%; 95% CI, -40 to -2), and C(trough) (-13%; 95% CI, -21 to -5). The interaction of St John's wort and digoxin varies within St John's wort preparations and doses and seems to be correlated with the dose, particularly of hyperforin.
St. Johns wort attenuates irinotecan-induced diarhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis
Article
  • Nov 2006
Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1beta, IL-2, IL-6), interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1beta, IL-2, IL-6, IFN-gamma and TNF-alpha and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1beta, IFN-gamma and TNF-alpha was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-alpha mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.