Studies on induction of lamotrigine metabolism in transgenic UGT1 mice Lamotrigine metabolism in transgenic UGT1 mice

U. A. Argikar, K. Senekeo-Effenberger, E. E. Larson, R. H. Tukey, Rory P Remmel

Research output: Contribution to journalArticle

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Abstract

A transgenic 'knock-in' mouse model expressing a human UGT1 locus (Tg-UGT1) was recently developed and validated. Although these animals express mouse UGT1A proteins, UGT1A4 is a pseudo-gene in mice. Therefore, Tg-UGT1 mice serve as a 'humanized' UGT1A4 animal model. Lamotrigine (LTG) is primarily metabolized to its N-glucuronide (LTGG) by hUGT1A4. This investigation aimed at examining the impact of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) activators on LTG glucuronidation in vivo and in vitro. Tg-UGT1 mice were administered the inducers phenobarbital (CAR), pregnenolone-16α-carbonitrile (PXR), WY-14643 (PPAR-α), ciglitazone (PPAR-γ), or L-165041 (PPAR-β), once daily for 3 or 4 days. Thereafter, LTG was administered orally and blood samples were collected over 24h. LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals. A three-fold increase in in vivo LTG clearance was seen after phenobarbital administration. In microsomes prepared from phenobarbital-treated Tg-UGT1 animals, 13-fold higher CLint (Vmax/Km) value was observed as compared with the untreated transgenic mice. A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone-16α- carbonitrile and WY-14643 treatment. This study demonstrates the successful application of Tg-UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of UGT1A4 substrates.

Original languageEnglish (US)
Pages (from-to)826-835
Number of pages10
JournalXenobiotica
Volume39
Issue number11
DOIs
StatePublished - Nov 1 2009

Fingerprint

Peroxisome Proliferator-Activated Receptors
Metabolism
Transgenic Mice
Animals
Phenobarbital
Pregnenolone Carbonitrile
Blood
4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid
Glucuronides
Liver
Liver Microsomes
Microsomes
Catalyst activity
Genes
lamotrigine
Animal Models
Substrates
Proteins
constitutive androstane receptor
pregnane X receptor

Keywords

  • Induction
  • Lamotrigine
  • N-glucuronide
  • Transgenic mice
  • Uridine glucuronosyl transferases (UGTs)

Cite this

Studies on induction of lamotrigine metabolism in transgenic UGT1 mice Lamotrigine metabolism in transgenic UGT1 mice. / Argikar, U. A.; Senekeo-Effenberger, K.; Larson, E. E.; Tukey, R. H.; Remmel, Rory P.

In: Xenobiotica, Vol. 39, No. 11, 01.11.2009, p. 826-835.

Research output: Contribution to journalArticle

Argikar, U. A. ; Senekeo-Effenberger, K. ; Larson, E. E. ; Tukey, R. H. ; Remmel, Rory P. / Studies on induction of lamotrigine metabolism in transgenic UGT1 mice Lamotrigine metabolism in transgenic UGT1 mice. In: Xenobiotica. 2009 ; Vol. 39, No. 11. pp. 826-835.
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