Abstract
Serum concentrations of valproic acid (VPA) are markedly decreased by coadministration of carbapenem antibiotics (CBPMs). Although inhibition of deconjugation of VPA-glucuronide (VPA-G) to VPA by CBPMs has been proposed as one of the mechanisms to account for this drug-drug interaction, little information is available on the mode of inhibition. In the present study, we characterized the enzyme involved in the deconjugation of VPA-G by using human and rat liver cytosol. It is suggested that 1) deconjugation activity inhibited by CBPMs may be selective for VPA-G, 2) deconjugation of VPA-G may be mediated by enzyme(s) other than β-glucuronidase, and 3) the irreversible inactivation may be responsible for the inhibition of deconjugation of VPA-G by CBPMs. Finally, the kinetic parameters for inactivation (K′app and kinact) were determined for four CBPMs of diverse structure from in vitro experiments. Based on the results of simulation analyses with these parameters and the degradation rate constant of the putative VPA-G deconjugation enzyme obtained from experiments using rats, it is probable that the deconjugation enzyme for VPA-G in the liver is rapidly and mostly inactivated by these CBPMs under clinical situations.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034231.
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ABBREVIATIONS:
- VPA
- valproic acid
- UGT
- UDP-glucuronosyl transferase
- UDP-GA
- UDP-glucuronic acid
- VPA-G
- valproic acid glucuronide
- CBPM
- carbapenem antibiotic
- DRPM
- doripenem
- SL
- saccharic acid 1,4-lactone
- PAPM
- panipenem
- MEPM
- meropenem
- BIPM
- biapenem
- MFA-G
- mefenamic acid glucuronide
- 4-MU
- 4-methylumbelliferone
- 4-MUG
- 4-methylumbelliferyl-β-d-glucuronide
- LC
- liquid chromatography
- MS/MS
- mass spectrometry
- VPAGase
- putative valproic acid glucuronide deconjugation enzyme.
- Received May 1, 2010.
- Accepted June 25, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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