St. John’s Wort Modulates the Toxicities and Pharmacokinetics of CPT-11 (Irinotecan) in Rats

Abstract

CPT-11 is a DNA topoisomerase I inhibitor for the therapy of colorectal cancer, whereas St. John's Wort (Hypericum perforatum, SJW) is a widely used herbal anti-depressant. This study aimed to investigate the effects of co-administered SJW on the toxicities and pharmacokinetics of CPT-11 and the underlying mechanisms. The body weight loss, gastrointestinal and hematological toxicities induced by CPT-11, and the pharmacokinetic parameters of CPT-11 were evaluated in rats pretreated with SJW or vehicle. Rats treated with CPT-11 alone experienced rapid decrease in body weight, whereas co-administration of SJW with CPT-11 resulted in lesser body weight loss. The gastrointestinal and hematological toxicities following CPT-11 injection were both alleviated in the presence of SJW. The rat pharmacokinetics of both CPT-11 and its metabolite SN-38 were significantly altered in presence of SJW. In conclusion, co-administered SJW significantly ameliorated the toxicities induced by CPT-11. The protective effect of SJW may be partially due to pharmacokinetic interaction between CPT-11 and SJW.

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

“…In cancer patients using SJW in combination with irinotecan, the plasma levels of SN-38, the active metabolite of irinotecan, were 42% lower [4]. The same effect was observed in rats, in which long-term (14 days) exposure to SJW resulted in a significantly lower maximum observed concentration (C max ) of both irinotecan and SN-38 [5]. In cancer patients, the degree of myelosuppression was substantially worse in the absence of SJW [4].…”

How are Interactions Taken into Account in Studies on Conventional and Complementary Therapies for Breast Cancer Patients with Menopausal Complaints?

“…breast cancer Direct keyword search: [7]or [8]or [9] On the basis of the title and abstract, we checked whether the article presented a controlled clinical study on supportive therapy for menopausal symptoms or, respectively, a corresponding review or meta-analysis. Subsequently the article was analysed as to whether the topic of interactions was recognisably taken into consideration.…”

“…However, potential interactions are, of course, not limited to complementary medicine, but also are involved in the substances of conventional medicine. Every 4th tumour patient is endangered by interactions between chemotherapy, supportive therapy and/or drugs for co-morbidities [8]. Accordingly in studies on new drugs, increasingly comprehensive lists of drugs and natural substances that should not be consumed during the study period are being compiled.…”

“…It could be expected that the consideration of interactions would have increased after the interactions of St. Johnʼs wort became known. However this is not the case, either in conventional supportive therapy or in complementary medicine [8].…”

Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process

“…Discontinuation of the precipitator usually brings enzyme levels back to normal, making the process reversible. Induction of the enzymes involved in the metabolism and transport of chemotherapeutic drugs irinotecan or imatinib is responsible for the lower plasma levels observed when each is concurrently administered with St John's Wort (78,79). On the other hand, inhibition of CYP3A4 by grapefruit juice was responsible for the increase in plasma levels of felodipine when a 5mg tablet was taken with the juice (80).…”