Letter to the Editor
St. John's wort and irinotecan-induced diarrhea
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.
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,
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,
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: firstname.lastname@example.org.
28 November 2006
Toxicology and Applied Pharmacology 220 (2007) 108
0041-008X/$ - see front matter © 2007 Elsevier Inc. All rights reserved.