A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-a inhibitor

Yang, X, Hu, Z, Xu, A, Duan, W, Zhu, Y, Huang, M, Sheu, F, Zhang, Q, Boelsterli, U, Bian, J, Chan, E, Li, X, Wang, J and Zhou, S 2006, 'A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-a inhibitor', Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 1, pp. 82-104.


Document type: Journal Article
Collection: Journal Articles

Title A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-a inhibitor
Author(s) Yang, X
Hu, Z
Xu, A
Duan, W
Zhu, Y
Huang, M
Sheu, F
Zhang, Q
Boelsterli, U
Bian, J
Chan, E
Li, X
Wang, J
Zhou, S
Year 2006
Journal name Journal of Pharmacology and Experimental Therapeutics
Volume number 319
Issue number 1
Start page 82
End page 104
Total pages 23
Publisher American Society for Pharmacology and Experimental Therapeutics
Abstract Dose-limiting diarrhea and myelosuppression compromise the success of irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino] carbonyloxycamptothecin) (CPT-11)-based chemotherapy. A recent pilot study indicates that thalidomide attenuates the toxicity of CPT-11 in cancer patients. This study aimed to investigate whether coadministered thalidomide modulated the toxicities of CPT-11 and the underlying mechanisms using several in vivo and in vitro models. Diarrhea, intestinal lesions, cytokine expression, and intestinal epithelial apoptosis were monitored. Coadministered thalidomide (100 mg/kg i.p. for 8 days) significantly attenuated body weight loss, myelosuppression, diarrhea, and intestinal histological lesions caused by CPT-11 (60 mg/kg i.v. for 4 days). This was accompanied by inhibition of tumor necrosis factor-a, interleukins 1 and 6 and interferon-?, and intestinal epithelial apoptosis. Coadministered thalidomide also significantly increased the systemic exposure of CPT-11 but decreased that of SN-38 (7-ethyl-10-hydroxycampothecin). It significantly reduced the biliary excretion and cecal exposure of CPT-11, SN-38, and SN-38 glucuronide. Thalidomide hydrolytic products inhibited hydrolysis of CPT-11 in rat liver microsomes but not in primary rat hepatocytes. In addition, thalidomide and its major hydrolytic products, such as phthaloyl glutamic acid (PGA), increased the intracellular accumulation of CPT-11 and SN-38 in primary rat hepatocytes. They also significantly decreased the transport of CPT-11 and SN-38 in Caco-2 and parental MDCKII cells. Thalidomide and PGA also significantly inhibited P-glycoprotein (PgP/MDR1), multidrug resistance-associated protein (MRP1)- and MRP2-mediated CPT-11 and SN-38 transport in MDCKII cells. These results provide insights into the pharmacodynamic and pharmacokinetic mechanisms for the protective effects of thalidomide against CPT-11-induced intestinal toxicity.
Subject Toxicology (incl. Clinical Toxicology)
DOI - identifier 10.1124/jpet.106.103606
ISSN 0022-3565
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