title: In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs.
abstract: 1. Our previous in vitro studies suggest that inhibition of the acylpeptide hydrolase (APEH) activity as valproic acid glucuronide (VPA-G) hydrolase by carbapenems in human liver cytosol is a key process for clinical drug-drug interaction (DDI) of valproic acid (VPA) with carbapenems. Here, we investigated whether in vivo DDI of VPA with meropenem (MEPM) was caused via inhibition of APEH in dogs. 2. More rapid decrease of plasma VPA levels and increased urinary excretion of VPA-G were observed after co-administration with MEPM compared with those after without co-administration, whereas the plasma level and bile excretion of VPA-G showed no change. 3. Dog VPA-G hydrolase activity, inhibited by carbapenems, was mainly located in cytosol from both the liver and kidney. APEH-immunodepleted cytosols lacked VPA-G hydrolase activity. Hepatic and renal APEH activity was negligible even at 24 h after dosing of MEPM to a dog. 4. In conclusion, DDI of VPA with carbapenems in dogs is caused by long-lasting inhibition of APEH-mediated VPA-G hydrolysis by carbapenems, which could explain the delayed recovery of plasma VPA levels to the therapeutic window even after discontinuation of carbapenems in humans.
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ikenaga
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fusegawa
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Ryoya
authors.initials: R
authors.lastname: Goda
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuga
authors.affiliation: a Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D015780:Carbapenems / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006868:Hydrolysis; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D000077731:Meropenem; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000097:blood* / Q000652:urine
chemical_list: D015780:Carbapenems; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D013845:Thienamycins; C041285:valproic acid glucuronide; D014635:Valproic Acid; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; D000077731:Meropenem
keywords: Drug–drug interaction; long-lasting inhibition; valproic acid glucuronide