Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: comparative effects of granisetron and ondansetron.
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 microl/min. Cisplatin (89 +/- 2.9 mg of cisplatin/m(2)) 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 continuous 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.
Castejon
A M
AM
Laboratory of Neuropharmacology and Clinical Pharmacology, Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas, Venezuela.
Paez
X
X
Hernandez
L
L
Cubeddu
L X
LX
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D017829:Granisetron / Q000494:pharmacology*; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000097:blood / Q000652:urine; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D017294:Ondansetron / Q000494:pharmacology*; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014839:Vomiting / Q000097:blood / Q000139:chemically induced
D000970:Antineoplastic Agents; D002945:Cisplatin; D017829:Granisetron; D006897:Hydroxyindoleacetic Acid; D017294:Ondansetron; D012701:Serotonin; D012702:Serotonin Antagonists