title: Pharmacokinetic, distribution, metabolism, and excretion of (Z)-2-amino-1,5-dihydro-1-methyl-5-[4-(mesyl)benzylidene]-4H-imidazol-4-one mesilate (ZLJ-601) in Sprague-Dawley rats.
abstract: (Z)-2-amino-1,5-dihydro-1-methyl-5-[4-(mesyl)benzylidene]-4H-imidazol-4-one mesilate (ZLJ-601) is an imidazolone COX/5-LOX inhibitor, which has excellent anti-inﬂammatory activity with an improved gastrointestinal safety profile. The purpose of this study was to evaluate the in vivo absorption, distribution, metabolism, and excretion of ZLJ-601 in Sprague-Dawley rats. After intravenous or intragastric administration to rats, the concentration of ZLJ-601 in plasma, bile, urine, feces and various types of tissues was detected by LC-MS. We also conducted the identification of metabolites using tandem mass spectrometry. After the intravenous administration, the t(1/2) ranged from 38.71 to 42.62 min and the AUC increased in a dose-proportional manner. After oral dosing, the plasma level of ZLJ-601 peaked at 28.33 min, having a C(max) value of 0.26 mg/l, and the bioavailability was only 4.92%. The highest tissue concentration of ZLJ-601 was observed in lung and kidney, but it was not found in brain. The majority of unchanged ZLJ-601 was excreted in urine (∼35.87%) within 36 h. Two main metabolites are the hydroxylation product and the glucuronide conjugate of the hydroxylation product.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Cuiyun
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry; D002853:Chromatography, Liquid; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008698:Mesylates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: C574554:(Z)-2-amino-1,5-dihydro-1-methyl-5-(4-(mesyl)benzylidene)-4H-imidazol-4-one mesilate; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D008698:Mesylates