Hensetron Mechanism of Action

Pharmacology: Tropisetron HCl is a highly potent and selective competitive antagonist of the 5-HT3 receptor with a potent antiemetic action similar to that of ondansetron but more prolonged. Some substances, including some chemotherapeutic agents, may trigger the release of serotonin (5-HT) from enterochromaffin-like cells in the visceral mucosa and initiate the emesis reflex. Moreover, its antiemetic effect may be related to the inhibition of the stimulation of vagus nerve in the area postrema by its direct block of CNS 5-HT3 receptors.
Genotoxicity: The literature reports that tropisetron HCl has no significant effect on the mouse bone marrow micronucleus, even at vitro high concentration, no chromosomal anomaly and mutagenic action have been observed.
Reproductive Toxicity: Animal reproductive toxicity test shows that it has potential embryotoxicity. It is not known whether it is excreted into human milk and women during lactation should not receive it.
Pharmacokinetics: Healthy volunteers administered tropisetron HCl IV, the elimination t_½ is about 7.3-30.3 hrs, the apparent volume of distribution (V) is about 400-600 L and the protein binding rate is about 59-71%.
The metabolism of tropisetron is linked to sparteine/debrisoquine polymorphism (cytochrome P-450D6). About 8% of the Caucasian population lacks the enzyme. The metabolism of tropisetron occurs by hydroxylation at the 5, 6 or 7 positions of its indole ring, followed by a conjugation reaction to the glucuronide or sulfate and excretion in the urine or bile (urine to feces ratio 5:1). The metabolites have greatly reduced potency for the 5-HT3 receptor and do not contribute to the pharmacological action of the drug. The elimination t_½ (β-phase) is about 7-10 hrs in normal metabolizers; in poor metabolizers this could be extended to 45 hrs. The total clearance rate is about 1 L/min, among which 10% is excreted in the kidney, in poor metabolizers, even the ratio of excretion in the kidney does not change, the total clearance reduces to be 0.1-0.2 L/min. The decrease may result in the 4-5 times of prolongation of clearance t_½, AUC increase 5-7 times and there are no significant changes in C_max and V with normal metabolizers. In poor metabolizers, the ratio of unchanged drug excreted via urine is larger in comparison with normal metabolizers.
During many days of administration of tropisetron HCl at dose of >10 mg twice daily, the metabolic capability of liver enzyme system involving in the metabolism of tropisetron may reach storable and may result in the increase of dose dependence of plasma drug concentration. However, even in poor metabolizers, the drug exposure at the dose still belong to the level well tolerated. Thus, it is unnecessary to worry about the drug accumulation of the regimen as 6-day courses of 5 mg/day.