title: Identification of valproic acid glucuronide hydrolase as a key enzyme for the interaction of valproic acid with carbapenem antibiotics.
abstract: Plasma levels of valproic acid (VPA) are decreased by concomitant use with carbapenem antibiotics, such as panipenem (PAPM). One of the plausible mechanisms of this interaction is the inhibition of VPA glucuronide (VPA-G) hydrolysis by carbapenems in the liver. To elucidate this interaction mechanism, we purified VPA-G hydrolase from human liver cytosol, in which the hydrolytic activity was mainly located. After chromatographic purification, the VPA-G hydrolase was identified as acylpeptide hydrolase (APEH). APEH-depleted cytosol, prepared by an immunodepletion method, completely lacked the hydrolytic activity. These results demonstrate that APEH is a single enzyme involved in PAPM-sensitive VPA-G hydrolysis in cytosol. In addition, the hydrolytic activity of recombinant human APEH was inhibited by PAPM and the inhibition profile by typical esterase inhibitors (diisopropyl fluorophosphate, 5,5'-dithiobis(2-nitrobenzoic acid), p-chloromercuribenzoic acid, and d-saccharic acid 1,4-lactone) was similar to that of human liver cytosol. Cytosolic VPA-G hydrolase activity was slightly inhibited by cholinesterase and carboxylesterase inhibitors. beta-Glucuronidase activity remained in APEH-depleted cytosol, whereas VPA-G hydrolase activity was completely abolished. Thus, either cholinesterase, carboxylesterase, or beta-glucuronidase in cytosol would not be involved in VPA-G hydrolysis. Taken together, APEH plays a major role in the PAPM-sensitive VPA-G hydrolysis in the liver. These findings suggest that APEH could be a key enzyme for the drug interaction of VPA with carbapenems via VPA-G hydrolysis.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo, Japan. tsukada.eiko.x7@daiichisankyo.co.jp
authors.forename: Eiko
authors.initials: E
authors.lastname: Suzuki
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Yamamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Kazuishi
authors.initials: K
authors.lastname: Kubota
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Miura
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D015153:Blotting, Western; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology; D014635:Valproic Acid / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D020719:Glucuronides; D014635:Valproic Acid; D006867:Hydrolases; D005966:Glucuronidase