Vol. 291, Issue 3, 960-966, December 1999

Use of Intravenous Microdialysis to Monitor Changes in Serotonin Release and Metabolism Induced by Cisplatin in Cancer Patients: Comparative Effects of Granisetron and Ondansetron¹

Ana M. Castejon, Ximena Paez, Luis Hernandez and Luigi X. Cubeddu

Laboratory of Neuropharmacology and Clinical Pharmacology, Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas, Venezuela (A.M.C., L.X.C.); and Laboratory of Behavioral Physiology, Universidad de los Andes, Merida, Venezuela (X.P., L.H.)

Serotonin [5-hydroxytryptamine (5-HT)] is involved in the production of emesis associated with cisplatin treatment. Serotonin released from intestinal enterochromaffin cells may act either directly on vagal afferents and/or pass to the circulation and stimulate central emetic centers. However, the role for circulating 5-HT has not been determined. In this study, i.v. microdialysis probes were used to investigate 1) cisplatin-induced changes in 5-HT release and metabolism assessed through changes in blood dialysate levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), 2) whether free 5-HT in blood increases after cisplatin, and 3) whether granisetron and ondansetron exert different effects on cisplatin-induced 5-HT release and metabolism. Control experiments conducted in 10 healthy volunteers revealed stable 5-HT and 5-HIAA dialysate levels for a period of 6 h. In patients with cancer (n = 16), baseline blood dialysate 5-HIAA concentrations averaged 2.98 ± 0.38 ng/ml, which were equivalent to a total of 94 ± 10 pg in the 30-min collection period at a flow rate of 1 µl/min. Cisplatin (89 ± 2.9 mg of cisplatin/m²) produced a gradual increase in blood dialysate 5-HIAA levels (104 ± 4% increase at 4 h). Increases in dialysate 5-HIAA were associated with increases in the urinary excretion of this metabolite. After cisplatin, dialysate 5-HIAA levels increased to 5.89 ± 0.5 ng/ml in granisetron and to 5.27 ± 0.9 ng/ml in ondansetron-treated patients (P > .1). Similar time courses and percentages of increase in blood dialysate and urinary 5-HIAA levels were observed in ondansetron- and granisetron-treated patients. Contrary to 5-HIAA, no significant increases in dialysate 5-HT were observed from 2 to 8 h after cisplatin either for the total group or for each of the groups separately. In conclusion, i.v. microdialysis probes coupled to HPLC-EC allowed the continuos monitoring of free-5-HT and 5-HIAA in blood. Cisplatin-induced increases in blood 5-HIAA were not associated with increases in 5-HT blood dialysates. These results argue against a possible action of free 5-HT in plasma on the chemoreceptor trigger zone (unprotected from the blood brain barrier) but support the view that 5-HT released within the intestinal wall triggers emesis after cisplatin. Our results argue against the view that at clinically effective doses, granisetron and ondansetron exert different actions on cisplatin-induced 5-HT release and metabolism.