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

Alimentary Pharmacology & Therapeutics
K M KochKathryn E E Kersey

Abstract

To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. 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. Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probe-metabolite/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. 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 associa...Continue Reading

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Citations

Apr 11, 2008·European Journal of Clinical Pharmacology·Takeshi KadokuraAkito Nishida
Apr 29, 2008·European Journal of Clinical Pharmacology·Takeshi KadokuraAkito Nishida
Jan 1, 2007·Women's Health·Lucinda A Harris, Lin Chang
Jun 7, 2013·Expert Opinion on Drug Metabolism & Toxicology·David C LambBin Zhao
Jan 9, 2007·Psychosomatics·Gary H WynnKelly L Cozza
Jan 25, 2007·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·M Camilleri
Jan 8, 2014·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Madhusudan Grover, Michael Camilleri
Jul 1, 2015·Nature Reviews. Gastroenterology & Hepatology·Jay R ThiagarajahAlan S Verkman
Jan 19, 2005·The American Journal of Gastroenterology·Lin ChangEmeran A Mayer
May 8, 2015·Therapeutic Advances in Gastroenterology·Yang Won Min, Poong-Lyul Rhee
Oct 26, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Nadine El-Ayache, James J Galligan
Feb 9, 2010·Expert Review of Gastroenterology & Hepatology·James H Lewis
Nov 17, 2019·International Journal of Molecular Sciences·Stephania ParedesNebojsa Nick Knezevic
Nov 13, 2015·Journal of Pharmacokinetics and Pharmacodynamics·Seong Heon LeeSeongwook Jeong

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