Abstract
To investigate the mechanism for the enhanced glucuronidation of valproic acid (VPA) by panipenem (PAPM), a carbapenem antibiotic, in rat liver, we carried out studies to investigate whether PAPM increases the activity of UDP-glucuronosyltransferase or the level of hepatic UDP-glucuronic acid (UDPGA) in rats. PAPM had no effect on the UDP-glucuronosyltransferase activity toward VPA both in vivo and in vitro. On the other hand, in vivo treatment with PAPM significantly increased the hepatic UDPGA level by about 1.7-fold (control: 434.5 ± 65.5 nmol/g of liver; PAPM-treated: 755.2 ± 92.3 nmol/g of liver). The in vitro formation of VPA glucuronide increased proportionally as a function of the UDPGA concentration up to 0.8 mM. Therefore, the increase in the level of hepatic UDPGA by PAPM is likely to be one of the causal factors for enhancing VPA glucuronidation in vivo.
Footnotes
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Send reprint requests to: Naotoshi Yamamura, Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd. 2-58, Hiromachi 1-chome Shinagawa-ku, Tokyo 140-8710, Japan. E-mail:yamamu{at}shina.sankyo.co.jp
- Abbreviations used are::
- PAPM
- panipenem
- BP
- betamipron
- VPA
- valproic acid
- VPA-Glu
- valproate glucuronide
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- UDP-glucuronic acid
- TLC
- thin-layer chromatography
- pNP
- p-nitrophenol
- pNP-Glu
- pNP glucuronide
- Received June 1, 2000.
- Accepted September 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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