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

Abstract

1. 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.

2. 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).

3. 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.

4. 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.

Keywords:

• Bioavailability
• dose proportionality
• preclinical pharmacokinetics
• liquid chromatography-mass spectrometry
• absorption

Acknowledgements

Authors appreciate the employees of the Kizhner Scientific Center for supplying substances (IQ-1 and IQ-18) and general consulting.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analysed during this study are included in this article. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.