Alosetron - How It Works
Clinical pharmacology details from the US FDA-approved label: how Alosetron works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Alosetron is a potent and selective 5-HT 3 receptor antagonist. 5-HT 3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of IBS. 5-HT 3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels, which results in the modulation of the enteric nervous system. The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, patients with IBS exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alose
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alosetron is a potent and selective 5-HT 3 receptor antagonist.
5-HT 3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations.
Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of IBS.
5-HT 3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels, which results in the modulation of the enteric nervous system.
The cause of IBS is unknown.
IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity.
Following distention of the rectum, patients with IBS exhibit pain and discomfort at lower volumes than healthy volunteers.
Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT 3 receptors.
12.2 Pharmacodynamics In healthy volunteers and patients with IBS, alosetron (2 mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time.
In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4 mg dose.
In patients with IBS, multiple oral dosages of alosetron (4 mg twice daily for 6.5 days) significantly increased colonic compliance.
Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin.
Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg administered orally twice daily.
This decrease was not statistically significant.
In another study utilizing alosetron 1 mg administered orally twice daily for 4 days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion.
However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production.
The clinical significance of these findings is unknown.
12.3 Pharmacokinetics The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 mg to 16 mg in healthy men.
The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily.
Absorption: Alosetron was rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range, 30% to > 90%).
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 mg to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily. Absorption: Alosetron was rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range, 30% to > 90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1 mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurred at 1 hour. In young women, the mean peak plasma concentration was approximately 9 ng/mL, with a similar time to peak. Plasma concentrations were 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men). Food Effects: Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes [see Dosage and Administration ] . Distribution: Alosetron demonstrates a volume of distribution of approximately 65 L to 95 L. Plasma protein binding is 82% over a concentration range of 20 ng/mL to 4,000 ng/mL. Metabolis