Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: Comparative effects of granisetron and ondansetron
Am. Castejon et al., Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: Comparative effects of granisetron and ondansetron, J PHARM EXP, 291(3), 1999, pp. 960-966
Citations number
38
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Serotonin [5-hydroxytryptamine (5-HT)] is involved in the production of eme
sis associated with cisplatin treatment. Serotonin released from intestinal
enterochromaffin cells may act either directly on vagal afferents and/or p
ass to the circulation and stimulate central emetic centers. However, the r
ole for circulating 5-HT has not been determined. In this study, i.v. micro
dialysis probes were used to investigate 1) cisplatin-induced changes in 5-
HT release and metabolism assessed through changes in blood dialysate level
s 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 c
ollection period at a flow rate of 1 ml/min. Cisplatin (89 +/- 2.9 mg of ci
splatin/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 cisplati
n, dialysate 5-HIAA levels increased to 5.89 +/- 0.5 ng/ml in granisetron a
nd 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 obser
ved 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 incre
ases in 5- HT blood dialysates. These results argue against a possible acti
on of free 5-HT in plasma on the chemoreceptor trigger zone (unprotected fr
om the blood brain barrier) but support the view that 5- HT released within
the intestinal wall triggers emesis after cisplatin. Our results argue aga
inst the view that at clinically effective doses, granisetron and ondansetr
on exert different actions on cisplatin-induced 5-HT release and metabolism
.