We have investigated the pharmacokinetics of a 5-day multiple oral dose of 5 mg
tropisetron capsule in patients with malignant tumour who had received
cisplatin single administration. Its
anti-emetic effects on acute and delayed
emesis and
vomiting were also investigated. During the 5 days after this administration, changes in the release and metabolism of
serotonin were investigated. The results may be summarized as follows: 1) The pharmacokinetic parameters of
tropisetron revealed no significant change in the data between day 1 and day 5. Also, the parameters were almost similar to those observed in healthy adult males (clinical phase I study); Cmax. T1/2 and AUC 0-24 hrs on day 1 were 9.1 +/- 2.1 ng/ml, 12.5 +/- 4.2 hrs, 85.5 +/- 22.7 ng.hr/ml, respectively. The urinary excretion of the parent
drug up until 24 hours after administration on day 1 was 3.8% of the dose administered and 2.9% of the total dose after the last administration; no difference in the urinary excretion rate was observed in healthy subjects. It was thus suggested that hydration accompanied by
cisplatin administration did not affect the pharmacokinetics of
tropisetron. 2) The changes in the amount of urinary excretion of 5-hydroxy-
indoleacetic acid (5-HIAA) during 5 days after
cisplatin administration were observed; urinary excretion of 5-HIAA increased 2.3 times (1.3-5.4 times) the baseline on the average during 6 to 12 hours on day 1. In 6 out of 10 patients, the increases in urinary excretion of 5-HIAA showed double or more the baseline during 2 to 5 days after
cisplatin administration.
Serotonin was thus deemed to be related to the development of delayed
emesis. 3) The
anti-emetic effects of
tropisetron on acute and delayed
emesis and
vomiting were rated as "markedly effective" in 6 out of 11 patients (54.6%) and "effective" in 1 out of 11 patients (9.1%) on day 1;
vomiting did not occur in any of these 7 patients.
Tropisetron also controlled
emesis and
vomiting during days 2-5, and was rated as "almost favorable" in 6 out of 11 patients (54.5%). Further, in 4 out of 6 patients, in whom the urinary excretion of 5-HIAA was increased on day 2 onwards,
vomiting did not occur during the time when the urinary excretion of 5-HIAA was increasing. On the basis of the above results,
tropisetron is deemed to have certain
antiemetic effects on delayed
vomiting as well. Its
5-HT3 receptor mediated mechanism was similarly seen to inhibit acute
nausea and
vomiting.