title: Metabolism and disposition of vilanterol, a long-acting β(2)-adrenoceptor agonist for inhalation use in humans.
abstract: The metabolism and disposition of vilanterol, a novel long-acting β(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 μg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration.
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom. andrew.w.harrell@gsk.com
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Harrell
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Siederer
authors.forename: Jo
authors.initials: J
authors.lastname: Bal
authors.forename: Nainesh H
authors.initials: NH
authors.lastname: Patel
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Young
authors.forename: Clive C
authors.initials: CC
authors.lastname: Felgate
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Pearce
authors.forename: Andy D
authors.initials: AD
authors.lastname: Roberts
authors.forename: Claire
authors.initials: C
authors.lastname: Beaumont
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Emmons
authors.forename: Adrian I
authors.initials: AI
authors.lastname: Pereira
authors.forename: Rodger D
authors.initials: RD
authors.lastname: Kempsford
mesh_terms: D000280:Administration, Inhalation; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D011817:Rabbits; D051381:Rats
chemical_list: D000319:Adrenergic beta-Antagonists; D001592:Benzyl Alcohols; D002250:Carbon Radioisotopes; D002722:Chlorobenzenes; C550468:vilanterol