Abstract
Background:The JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and its sodium salt exhibit antioxidant, hemorheological, endothelium-protective, anti-inflammatory, neuroprotective, and cardioprotective properties; however, no published reports describe their tissue distribution. We investigated the biodisposition of IQ-1 and its major metabolite, 11H-indeno[1,2-b]quinoxalin-11-one (IQ-18), in Wistar rats after a single oral 50 mg/kg dose of IQ-1.Methods:Male adult Wistar rats (230–260 g) received IQ-1 orally (50 mg/kg). Arterial blood (from the carotid artery), tissues (liver, kidney, heart, brain, lung, spleen, skeletal muscle, adipose tissue, and duodenum), mesenteric lymph, bile, and blood samples from the portal vein and inferior vena cava were collected following oral administration of 50 mg/kg IQ-1. Chromatographic separation was carried out on an EC Nucleodur C8 ec LC column (150 × 4.6 mm, 5 µm; Macherey-Nagel, Germany). IQ-1 and IQ-18 were quantified by validated LC-MS/MS method using a LC-20 Prominence system (Shimadzu) and a mass spectrometer 3200 QTRAP (AB Sciex). Analyst 1.6 and MultiQuant 2.1 (AB Sciex) handled data acquisition and analysis. Non-compartmental pharmacokinetic parameters were calculated with WinNonlin 5.2 (Pharsight). Statistics (Mann–Whitney U test; p < 0.05) were performed in Statistica 12.Results:The plasma pharmacokinetic parameters for IQ-1 were as follows: Cmax, 59.69 ng/mL; Tmax, 1 h; and T1/2, 5.58 h. IQ-1 was metabolized to IQ-18, which reached a plasma Cmax of 2464.06 ng/mL at 8 h. Both compounds were widely distributed in tissues, with the highest tissue-to-plasma ratio observed in the liver. The Tmax values were 0.5–1 h for IQ-1 and 4–8 h for IQ-18. These data may indicate predominant absorption via the portal vein, extensive hepatic metabolism, and a substantial reduction in the concentrations of both compounds in venous blood following hepatic passage.Conclusion:Our results provide valuable insights into the pharmacokinetic profile of IQ-1, which may inform future clinical trials.