title: The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.
abstract: The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08μg/mL at 0.25-0.5h post-dose with an AUCinfof 1.74±0.52μgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08μg/mL at 0.25h post-dose with an AUCinfof 1.94±0.22μgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans.
authors.affiliation: Evotec (UK) Ltd, 114 Innovation Drive, Abingdon, Oxfordshire OX14 4RZ, UK. Electronic address: anthony.dickie@evotec.com.
authors.forename: A P
authors.initials: AP
authors.lastname: Dickie
authors.affiliation: Nestlé Skin Health R&D, Les Templiers, Route des Colles BP 87, F-06902 Sophia-Antipolis, France.
authors.forename: C E
authors.initials: CE
authors.lastname: Wilson
authors.affiliation: Evotec International GmbH, Manfred Eigen Campus, Essener Bogen 7, Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schreiter
authors.affiliation: Evotec International GmbH, Manfred Eigen Campus, Essener Bogen 7, Hamburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wehr
authors.affiliation: Yecuris Corporation, PO Box 4645, Tualatin, OR 97062, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Yecuris Corporation, PO Box 4645, Tualatin, OR 97062, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bial
authors.affiliation: CEVEC Pharmaceuticals GmbH, Gottfried-Hagen-Str. 60-62, 51105 Cologne, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Scheer
authors.affiliation: Dept. of Surgery and Cancer, Imperial College, London, UK.
authors.forename: I D
authors.initials: ID
authors.lastname: Wilson
authors.affiliation: Evotec (UK) Ltd, 114 Innovation Drive, Abingdon, Oxfordshire OX14 4RZ, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Riley
mesh_terms: D000818:Animals; D002678:Chimera / Q000097:blood*; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood* / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013045:Species Specificity
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; C473384:lumiracoxib
keywords: Glucuronide conjugation; Reactive intermediates; Taurine conjugation