Enhanced gastric retention of solid resin beads as a marker for emetic potential of agents in rats.
Whereas nausea and emesis are burdensome side effects that lead to poor treatment compliance especially in chemotherapy, it is difficult to predict the emetic potential of agents in rats and mice because rodents do not vomit. We examined the effect of emetics on gastric retention and role of serotonin (5-hydroxytryptamine, 5-HT)<inf>3</inf> receptor in chemotherapeutic-induced enhancement of gastric retention in rats. The gastric retention of solid material was determined using resin beads, which were suitable to beads made with metals or glasses in size, hardness and weight. Each rat was orally given distilled water (0.5 ml/rat) containing 40 resin beads via a plastic feeding tube. The stomach was removed at 1 hr post-dose and cut along the greater curvature under carbon dioxide anesthesia. Beads were given immediately after administration of the drugs except with cisplatin, when there was a 1 hr delay. Cancer chemotherapeutics including cisplatin(0.1-3 mg/kg i.v.) and doxorubicin(0.3-10 mg/kg i.v.) and a nauseant, copper sulfate(1-30 mg/kg p.o.) enhanced gastric retention of beads. Ondansetron, a 5-HT<inf>3</inf> receptor antagonist, dose-dependently antagonized the enhanced gastric retention by cisplatin and doxorubicin. The copper sulfate-induced enhancement was also reversed by ondansetron. Our results suggest that 5-HT<inf>3</inf> receptors mediate the cancer chemotherapeutic-enhanced gastric retention of solid material in rats. This implicates that the gastric retention of solid material is a useful marker to predict the potential of compounds to induce nausea and/or emesis in non-vomiting rodents.
Department of Comparative Pathophysiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. akentaro@mil.ecc.u-tokyo.ac.jp
Kentaro
K
Ando
Kan
K
Takagi
Hirokazu
H
Tsubone
D000758:Anesthesia / Q000379:methods; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D002245:Carbon Dioxide / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D019327:Copper Sulfate / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004639:Emetics / Q000494:pharmacology*; D005746:Gastric Emptying / Q000187:drug effects*; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D008863:Microspheres; D009325:Nausea / Q000139:chemically induced; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects*; D014839:Vomiting / Q000139:chemically induced
D000932:Antiemetics; D004639:Emetics; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D002245:Carbon Dioxide; D017294:Ondansetron; D004317:Doxorubicin; D019327:Copper Sulfate; D002945:Cisplatin