title: Novel organic nitrate prodrug 4(R)-N-(2-Nitroxyethyl)-2-oxothiazolidine-4-carboxamide (RS-7897) serves as a xenobiotic substrate for pyroglutamyl aminopeptidase I in dogs.
abstract: RS-7897, a novel organic nitrate, structurally contains aminoethylnitrate (AEN) and L-2-oxothiazolidine-4-carboxylic acid (L-OTCA), which are linked together via an amide bond. Vasodilating activity of RS-7897 was 130 times weaker than that of AEN in vitro, while in vivo it was comparable to but longer lasting than those of AEN and nitroglycerin in anesthetized dogs. Intravenous administration of RS-7897 to dogs resulted in the appearance in plasma of AEN, which decreased with about 2.5 times longer t(1/2) (0.49 h) than that after administration of AEN itself. The T(max) value of AEN (0.25 h) after RS-7897 dosing agreed with the time showing the maximum vasodilating effect, indicating that RS-7897 serves as a prodrug releasing AEN slowly in vivo. The activity to hydrolyze RS-7897 to AEN and L-OTCA was localized in the cytosolic fractions of dog tissues, inhibited by thiol-blocking agents and was strongly inhibited by thyrotropin-releasing hormone, a substrate of pyroglutamyl aminopeptidase I (PAP-I). Furthermore, the RS-7897-hydrolyzing activity in dog liver cytosol was completely inhibited by an antibody against rat PAP-I. Therefore, it was found that PAP-I is involved in bioactivation of RS-7897 by amide bond hydrolysis, recognizing the sulfur-substituted L-pyroglutamyl moiety (L-OTCA) of this xenobiotic substrate.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. koujia@shina.sankyo.co.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Toshio
authors.initials: T
authors.lastname: Terao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yorikane
authors.forename: Taro
authors.initials: T
authors.lastname: Tokui
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda