Alosetron

Alosetron is a potent and selective 5-HT₃ receptor antagonist. 5-HT₃ 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-HT₃ 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-HT₃ receptors.

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.

The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 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.

Distribution

Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL.

Metabolism and Elimination

Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in patients with IBS confirmed that alosetron clearance is minimally influenced by doses up to 8 mg.

Renal elimination of unchanged alosetron accounts for only 13% of the dose. Renal clearance is approximately 112 mL/min.

A study with ¹⁴C-labeled alosetron in Caucasian males (n = 3) and females (n = 3) and an Asian male (n = 1) showed similar serum metabolite profiles. Unchanged alosetron was the major component in serum, with other metabolites being present at low concentrations, none amounting to more than 15% of the unmetabolized alosetron concentration. The circulating metabolites were identified as 6-hydroxy glucuronide, 6-hydroxy sulphate, 7-hydroxy sulphate, hydroxymethyl imidazole, and mono- and bis-oxygenated imidazole derivatives of alosetron. The metabolites are unlikely to contribute to the biological activity of alosetron. Of the circulating Phase I metabolites, only the hydroxymethyl imidazole has weak pharmacological activity, around 10-fold less potent than alosetron. Total recovery of radioactivity in the excreta was 85 ± 6%. The majority of the radiolabeled dose is excreted in the urine (74 ± 5%). The major urinary metabolites were the 6-hydroxy glucuronide and the mono- and bis-oxygenated imidazole derivatives of alosetron. 11 ± 4% of the radiolabeled dose was excreted in the feces with less than 1% of the dose being excreted as the unchanged alosetron.

Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non-CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism (62 to 97% of alosetron clearance) based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine.