Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

Authors

  • Phisit Khemawoot,

    1. Department of Medicinal Informatics, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan
    Search for more papers by this author
  • Chiharu Maruyama,

    1. Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
    Search for more papers by this author
  • Hirotaka Tsukada,

    1. Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
    Search for more papers by this author
  • Hiroyo Noda,

    1. Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
    Search for more papers by this author
  • Junko Ishizaki,

    1. Department of Pharmacy and Health Science, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, 920-1192, Japan
    Search for more papers by this author
  • Koichi Yokogawa,

    1. Department of Medicinal Informatics, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan
    2. Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
    Search for more papers by this author
  • Ken-ichi Miyamoto

    Corresponding author
    1. Department of Medicinal Informatics, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan
    2. Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
    • Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1, Takara-machi, Kanazawa 920-8641, Japan
    Search for more papers by this author

Abstract

The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G. Copyright © 2007 John Wiley & Sons, Ltd.

Ancillary