Dose proportionality and bioavailability of quinoxaline-based JNK inhibitor after single oral and intravenous administration in rats.

Abstract

The dose proportionality and bioavailability of the potential anti-inflammatory and neuroprotective JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) were evaluated by comparing pharmacokinetic parameters after single oral (25, 50 and 100 mg/kg) and intravenous (1 mg/kg) IQ-1 administration in rats.IQ-1 and its major metabolite ketone 11H-indeno[1,2-b]quinoxalin-11-one (IQ-18) were isolated from plasma samples by liquid-liquid extraction. IQ-1 (E-isomer) and IQ-18 were simultaneously quantified in plasma by the validated method of liquid chromatography with triple quadrupole mass spectrometry (HPLC-MS/MS).The absolute bioavailability of IQ-1 was < 1.5%. C_max values were 24.72 ± 4.30, 25.66 ± 7.11 and 37.61 ± 3.53 ng/mL after single oral administration of IQ-1 at doses of 25, 50 and 100 mg/kg, respectively. IQ-1 exhibited dose proportionality at 50-100 mg/kg dose levels, whereas its pharmacokinetics was not dose proportional over the range of 25-50 mg/kg. IQ-18 demonstrated the invariance of the dose-normalized Cmax.In this study we systematically elucidated the absorption characteristics of IQ-1 in rat gastrointestinal tract and provided better understanding of IQ-1 pharmacology for the future development of a new formulations and therapeutic optimisation.