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St. John's wort and irinotecan-induced diarrhea

Authors:
  • Pinnacle Dermatology
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,
225237.
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, 15001504.
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,
12471249.
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, 11051107.
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, 546557.
Piscitelli, S.C., Burstein, A.H., Chiatt, D., Alfaro, R.M., Falloon, J., 2000.
Indinavir concentrations and St. John's wort. Lancet 355, 547548.
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, 518524.
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. ...
... 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]. ...
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.
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