Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Abstract

SUMMARYAim: To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. Methods: Thirty healthy men and women received 1 mg oral alosetron twice-daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe-substrate and metabolite concentrations were measured after each cocktail dose. Results: Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probemetabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N-acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration. Conclusions: Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450-mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2.

The metabolism of the 5HT3antagonists ondansetron, alosetron and GR87442 I: A comparison ofin vitroandin vivometabolism andin vitroenzyme kinetics in rat, dog and human hepatocytes, microsomes and recombinant human enzymes

“…Quantitative differences in the production of metabolites of the 5HT 3 antagonists were apparent between in vitro systems. Neither microsomes nor hepatocytes completely reflected the quantitative in vivo metabolite profile of the 5HT 3 antagonists as previously reported in pre-clinical species or human (Wolf 2000;Koch et al 2004;Ismail et al 2005). In general, the production of more lipophilic, CYP3A4 mediated metabolites, especially carbonyl metabolites, predominated in microsomes compared with hepatocytes.…”

“…Alosetron is transformed into a large number of phase I and sequential phase II metabolites in pre-clinical species and man, with no single metabolite occurring at levels greater than 15% of the dose (Ismail et al 2005). Metabolically vulnerable sites exist on both the tricyclic pyrido-indol nucleus and the imidazole group of alosetron, and metabolism is primarily CYP-mediated (Koch et al 2004). As with ondansetron, hydroxylation of the tricyclic, pyridoindole ring system occurs as a predominant route of metabolism.…”

Efficacy and Safety of 5-Hydroxytryptamine 3 Receptor Antagonists in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Several factors have been suggested for these differences [39]. They include significant retardation by alosetron of small intestinal and colonic transit in women with IBS-D as compared with men, i.e., sex partly contributes to differences in the serotonergic control of intestinal and colonic transit in patients with D-IBS [40], more systemic exposure to alosetron was associated with inhibition of cytochrome P450 CYP1A2 in women than in men [41], and brain responses to visceral stimulation by alosetron in IBS are based on sex [42]. The activation of brain networks involved with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli differ in male and female patients with IBS [43].…”

The metabolism of the 5HT3antagonists, ondansetron, alosetron and GR87442 II: Investigation into thein vitromethods used to predict thein vivohepatic clearance of ondansetron, alosetron and GR87442 in the rat, dog and human

“…The reported clearance of ondansetron in the patient population appears to vary approximately 3-fold and was between 3 and 10 ml/min/kg (de Alwis et al 1998). A similar potential correlation with age was also reported for alosetron (Koch et al 2004). The hepatocytes used in the current studies were obtained from a cohort of older patients with the majority of the patients (15 out of 21) older than 55 years of age.…”