title: Characterization of inhibitory effect of carbapenem antibiotics on the deconjugation of valproic acid glucuronide.
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 k(inact)) 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.
authors.affiliation: The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Masuo
authors.forename: Kousei
authors.initials: K
authors.lastname: Ito
authors.forename: Takehito
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hisaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Honma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D014635:Valproic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D015780:Carbapenems; C041285:valproic acid glucuronide; D014635:Valproic Acid; D005966:Glucuronidase