Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin

  • Hironori Nakamura
  • Haruko Yokoyama
  • Risa Takayanagi
  • Koichi Yoshimoto
  • Akihiro Nakajima
  • Kiyoshi Okuyama
  • Osamu Iwase
  • Yasuhiko Yamada
Original Paper

Abstract

5-HT3 receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t1/2), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT3 receptor antagonists, as those effects are not based solely on the t1/2 value. We theoretically evaluated the antiemetic effects of three 5-HT3 receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT3 receptor occupancy of serotonin. We estimated the 5-HT3 receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT3 receptor antagonist and the time course of concentration of serotonin near the 5-HT3 receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT3 receptor antagonist was evaluated based on the normal level of 5-HT3 receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m2 of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT3 receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m2 of cisplatin.

Keywords

5-HT3 receptor antagonist Antiemetic effect Constipation Cisplatin 5-HT3 receptor occupancy of serotonin 

References

  1. Andrews PL, Rapeport WG, Sanger GJ (1988) Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Sci 9(9):334–341 (pii:0165-6147(88)90106-X)CrossRefPubMedGoogle Scholar
  2. Basch E, Hesketh PJ, Kris MG, Prestrud AA, Temin S, Lyman GH (2011) Antiemetics: American society of clinical oncology clinical practice guideline update. J Oncol Pract/Am Soc Clin Oncol 7(6):395–398. doi:10.1200/JOP.2011.000397 CrossRefGoogle Scholar
  3. Cubeddu LX (1996) Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. Oncology 53(Suppl 1):18–25CrossRefPubMedGoogle Scholar
  4. Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL (1990) Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 322(12):810–816. doi:10.1056/NEJM199003223221204 CrossRefPubMedGoogle Scholar
  5. Cubeddu LX, Hoffmann IS, Fuenmayor NT, Malave JJ (1992) Changes in serotonin metabolism in cancer patients: its relationship to nausea and vomiting induced by chemotherapeutic drugs. Br J Cancer 66(1):198–203CrossRefPubMedCentralPubMedGoogle Scholar
  6. du Bois A, Vach W, Kiechle M, Cramer-Giraud U, Meerpohl HG (1996) Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis. Oncology 53(Suppl 1):46–50CrossRefPubMedGoogle Scholar
  7. Igarashi S, Tanaka K, Yamamura H, Sawai K, Isobe M, Masui H, Kataoka H, Ishikawa M, Oka T (1992) Phase I study of Y-25130, a new 5-HT3 receptor antagonist––single intravenous administration. Clin Rep 26(6):2535–2547Google Scholar
  8. Kumakura H, Koyanagi J, Nishioka Y, Sato M, Nakajima T, Nakahira K, Tateno M (1990) Phase I study of granisetron (second report)––pharmacokinetics of granisetron following single and repeat intravenous drip infusion in Japanese healthy volunteers. Rinsho Iyaku 6(Suppl. 5):25–34Google Scholar
  9. Likun Z, Xiang J, Yi B, Xin D, Tao ZL (2011) A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults. Oncologist 16(2):207–216. doi:10.1634/theoncologist.2010-0198 CrossRefPubMedCentralPubMedGoogle Scholar
  10. Martin M (1996) The severity and pattern of emesis following different cytotoxic agents. Oncology 53(Suppl 1):26–31CrossRefPubMedGoogle Scholar
  11. Nakamura H, Yokoyama H, Yoshimoto K, Nakajima A, Okuyama K, Iwase O, Yamada Y (2013) Method for individualized evaluation of antiemetic effect induced by 5-HT3 receptor antagonist. Biol pharm Bull 36(5):780–787CrossRefPubMedGoogle Scholar
  12. Resnick RH, Gray SJ (1961) Distribution of serotonin (5-hydroxytryptamine) in the human gastrointestinal tract. Gastroenterology 41:119–121PubMedGoogle Scholar
  13. Sakamori M, Takehara S, Setoguchi M (1992) High affinity binding of Y-25130 for serotonin 3 receptor. Folia Pharmacologica Japonica 100(2):137–142CrossRefPubMedGoogle Scholar
  14. Shah A, DeGroot T, Apseloff G (2006) Pharmacokinetic evaluation and safety profile of a 15-minute versus 30-second infusion of palonosetron in healthy subjects. J Clin Pharmacol 46(10):1139–1145. doi:10.1177/0091270006291625 CrossRefPubMedGoogle Scholar
  15. Yamada Y, Sugiura M, Higo K, Ozeki T, Takayanagi R, Okuyama K, Yamamoto K, Satoh H, Sawada Y, Iga T (2004) Receptor occupancy theory-based analysis of antiemetic effects and standard doses of 5-HT3 receptor antagonists in cancer patients. Cancer Chemother Pharmacol 54(2):185–190. doi:10.1007/s00280-004-0798-x CrossRefPubMedGoogle Scholar
  16. Yamada Y, Fujita M, Okuyama K, Takayanagi R, Ozeki T, Yokoyama H, Iga T (2007) Analysis of antiemetic effect of various dosage regimens of azasetron hydrochloride based on 5-HT3 receptor occupancy of serotonin. Yakugaku Zasshi 127(2):353–357 (pii:JST.JSTAGE/yakushi/127.353)CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag France 2014

Authors and Affiliations

  • Hironori Nakamura
    • 1
  • Haruko Yokoyama
    • 1
  • Risa Takayanagi
    • 1
  • Koichi Yoshimoto
    • 2
  • Akihiro Nakajima
    • 3
  • Kiyoshi Okuyama
    • 2
  • Osamu Iwase
    • 3
  • Yasuhiko Yamada
    • 1
  1. 1.Department of Clinical Evaluation of Drug Efficacy, School of PharmacyTokyo University of Pharmacy and Life SciencesHachiojiJapan
  2. 2.Department of PharmacyTokyo Medical University Hachioji Medical CenterHachiojiJapan
  3. 3.Department of HematologyTokyo Medical University Hachioji Medical CenterHachiojiJapan

Personalised recommendations