title: Exploring the roles of UGT1A1 and UGT1A3 in oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor.
abstract: Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders. Substantial variability in the oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes, is largely unaccounted for by clinical variables. A study of 41 patients, 78% (32/41) of whom were non-Hispanic whites, with mild to moderate asthma identified an association of UGT1A1*28 and UGT1A3*2 with the oral clearance of GSK2190915 (P=3.8×10⁻⁴ and 1.2×10⁻⁵, respectively). However, in a subsequent replication study of 403 non-Hispanic white patients with asthma, we failed to observe a statistically significant association between oral clearance of GSK2190915 and either UGT1A1*28 or UGT1A3*2 (P>0.05). Therefore, genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified.
authors.affiliation: aStatistical Genetics bGenetics, GlaxoSmithKline, Research Triangle Park, North Carolina cGenetics, GlaxoSmithKline, Philadelphia, Pennsylvania, USA dClinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stockley Park eClinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Mosteller
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Condreay
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Harris
authors.forename: Claire
authors.initials: C
authors.lastname: Ambery
authors.forename: Misba
authors.initials: M
authors.lastname: Beerahee
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D056726:Genetic Association Studies; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008875:Middle Aged; D010421:Pentanoic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D007211:Indoles; D010421:Pentanoic Acids; D000099148:UGT1A1 Enzyme; C552410:3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; C122075:UDP-glucuronosyltransferase, UGT1A3