Human Carboxymethylenebutenolidase as a Bioactivating Hydrolase of Olmesartan Medoxomil in Liver and Intestine

• Published in: The Journal of biological chemistry Vol. 285; no. 16; pp. 11892 - 11902
• Main Authors: Ishizuka, Tomoko, Fujimori, Izumi, Kato, Mitsunori, Noji-Sakikawa, Chisa, Saito, Motoko, Yoshigae, Yasushi, Kubota, Kazuishi, Kurihara, Atsushi, Izumi, Takashi, Ikeda, Toshihiko, Okazaki, Osamu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.04.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Activation; Amino Acid Sequence; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics; Biotransformation; Carboxylic Ester Hydrolases - antagonists & inhibitors; Carboxylic Ester Hydrolases - genetics; Carboxylic Ester Hydrolases - isolation & purification; Carboxylic Ester Hydrolases - metabolism; Cell Line; CMBL; Cytosol - enzymology; DNA Primers - genetics; Enzyme Inhibitors - pharmacology; Enzymes; Enzymology; Esterase; Female; Humans; Identification; Imidazoles - chemistry; Imidazoles - pharmacokinetics; In Vitro Techniques; Intestines - enzymology; Kinetics; Liver - enzymology; Male; Metabolism/Drug; Molecular Sequence Data; Mutagenesis, Site-Directed; Olmesartan Medoxomil; Pregnancy; Prodrug; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Protein/Purification; Pseudomonas; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sequence Homology, Amino Acid; Site-directed Mutagenesis; Tetrazoles - chemistry; Tetrazoles - pharmacokinetics; Tissue Distribution; Xenobiotics; Site-directed Mutagenesis; Enzymes; Esterase; Metabolism/Drug; Protein/Purification; Activation; Identification; CMBL; Prodrug; Xenobiotics

Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the identification and characterization of the OM bioactivating enzyme that hydrolyzes the prodrug and converts to its pharmacologically active me...