Vol. 292, Issue 3, 1002-1007, March 2000

Probable Involvement of the 5-Hydroxytryptamine₄ Receptor in Methotrexate-Induced Delayed Emesis in Dogs

Hisashi Yamakuni, Hiroe Sawai, Yasue Maeda, Katsunori Imazumi, Hiroyuki Sakuma, Masahiko Matsuo, Seitaro Mutoh and Jiro Seki

Department of Metabolic Diseases, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan

Delayed emesis in cancer patients undergoing chemotherapy remains a significant problem. The pathogenesis of delayed emesis is still obscure. It was recently demonstrated that methotrexate (MTX), an anticancer drug, evoked delayed emesis in dogs in a manner similar to its actions in humans. We evaluated the antiemetic activity of FK1052, a potent antagonist for both the 5-hydroxytryptamine (HT)₃ and 5-HT₄ receptors, on delayed emesis induced by MTX in beagle dogs. Animal behavior was recorded for 3 days using a video camera. Delayed emesis lasting up to 72 h was observed in dogs treated with MTX (2.5 mg/kg i.v.), but acute emesis did not occur. The following antiemetics, at the dose that prevents cisplatin-induced acute emesis in dogs, were administered i.v. as multiple injections every 12 h during days 2 to 3. FK1052 (1 and 3.2 mg/kg) significantly reduced the emetic episodes caused by MTX, whereas ondansetron (1 mg/kg), a selective 5-HT₃ receptor antagonist, was not effective. The emetic episodes induced by MTX were also inhibited by another 5-HT_3/4 receptor antagonist, tropisetron (1 mg/kg). CP-122,721 (0.1 mg/kg), a potent selective tachykinin NK₁ receptor antagonist, significantly reduced the emetic responses to MTX. Copper sulfate-induced emesis in dogs was also prevented by FK1052, tropisetron, and CP-122,721 but not by ondansetron. FK1052, tropisetron, and ondansetron had negligible affinity for the NK₁ receptor at 1 µM. These results suggest that the 5-HT₄ receptor may be in part involved in the production of delayed emesis induced by MTX in dogs and that FK1052 may be a useful drug against both acute and delayed emesis induced by cancer chemotherapy.