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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

A Mechanistic Study on Reduced Toxicity of Irinotecan by Coadministered Thalidomide, a Tumor Necrosis Factor- Inhibitor

Department of Pharmacy (X.-X.Y., Z.-P.H., E.C., S.-F.Z.) and Department of Biological Science (F.-S.S.), Faculty of Science, National University of Singapore, Singapore, Singapore; Department of Biochemistry (W.D.) and Department of Pharmacology (Y.-Z.Z., J.-S.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Biochemistry, School of Life Sciences (A.-L.X.) and Institute of Clinical Pharmacology (M.H.), Sun Yat-sen University, Guangzhou, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China (Q.Z., J.-C.W.); and Department of Maternal Medicine, Affiliated Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China (X.L.)

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-, 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.

Address correspondence to: Dr. Shu-Feng Zhou, Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543. E-mail: shufengzhou2006{at}hotmail.com