title: Inhibition mechanism of carbapenem antibiotics on acylpeptide hydrolase, a key enzyme in the interaction with valproic acid.
abstract: We have reported that inhibition of acylpeptide hydrolase (APEH), identified as valproic acid glucuronide hydrolase in human liver cytosol, by carbapenem antibiotics could lead to a decrease of plasma levels of valproic acid. In this study, we examined the inhibition mechanism using human liver cytosol and purified porcine APEH with a similar property to human counterpart.        After preincubation of human liver cytosol with panipenem or meropenem for 30 min, the inhibition of APEH activity was 20-fold stronger than that without preincubation. Porcine APEH activity inhibited by meropenem did not recover after dialysis. Meropenem bound to porcine APEH and the binding was blocked by a serine hydrolase inhibitor, diisopropyl fluorophosphate.        Open β-lactam ring form of meropenem did not affect APEH activity in human liver cytosol. Likewise, other antibiotics, which have a different heterocycle adjacent to the β-lactam ring with an opposite configuration of the side chain from carbapenems, did not inhibit APEH activity.        In conclusion, carbapenems inhibit APEH in both reversible and true irreversible manner and the irreversible inhibition is partially explained by binding to the active serine of APEH. The closed β-lactam ring is essential for inhibition and the heterocycle and/or the configuration of side chain would be important.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Tokyo, Japan. tsukada.eiko.x7@daiichisankyo.co.jp
authors.forename: Eiko
authors.initials: E
authors.lastname: Suzuki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Yamamura
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000818:Animals; D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D003956:Dialysis; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007531:Isoflurophate / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D000077731:Meropenem; D010447:Peptide Hydrolases / Q000378:metabolism*; D034421:Sus scrofa; D013845:Thienamycins / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D014635:Valproic Acid / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015780:Carbapenems; D013845:Thienamycins; D007531:Isoflurophate; D014635:Valproic Acid; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; D000077731:Meropenem