PT  - JOURNAL ARTICLE
AU  - Yusuke Masuo
AU  - Kousei Ito
AU  - Takehito Yamamoto
AU  - Akihiro Hisaka
AU  - Masashi Honma
AU  - Hiroshi Suzuki
TI  - Characterization of Inhibitory Effect of Carbapenem Antibiotics on the Deconjugation of Valproic Acid Glucuronide
AID  - 10.1124/dmd.110.034231
DP  - 2010 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1828--1835
VI  - 38
IP  - 10
4099  - http://dmd.aspetjournals.org/content/38/10/1828.short
4100  - http://dmd.aspetjournals.org/content/38/10/1828.full
SO  - Drug Metab Dispos2010 Oct 01; 38
AB  - 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.