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Arch Toxicol. 2018 Jun;92(6):1953-1967. doi: 10.1007/s00204-018-2212-1. Epub 2018 May 2.

The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice.

Author information

1
Nestlé Skin Health R&D, Les Templiers, Route des Colles, BP 87, 06902, Sophia-Antipolis, France. claire.wilson@galderma.com.
2
Evotec (UK) Ltd, 114 Innovation Drive, Abingdon, Oxfordshire, OX14 4RZ, UK.
3
Evotec International GmbH, Manfred Eigen Campus, Essener Bogen 7, Hamburg, Germany.
4
Yecuris Corporation, PO Box 4645, Tualatin, OR, 97062, USA.
5
CEVEC Pharmaceuticals GmbH, Gottfried-Hagen-Str. 60-62, 51105, Cologne, Germany.
6
Department of Surgery and Cancer, Imperial College, Exhibition Rd, South Kensington, London, SW7 2AZ, UK.
7
Evotec (UK) Ltd, Alderley Park, Nether Alderley, Cheshire, SK10 4TG, UK.

Abstract

The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. 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 in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as 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 model for assessing the biotransformation of such compounds in humans.

KEYWORDS:

Humanized mice; Liver; Metabolism; Pharmacokinetics; Reactive metabolites

PMID:
29721588
DOI:
10.1007/s00204-018-2212-1

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