Quantitation of imidazo[1,2‐a]quinoxaline derivatives in human and rat plasma using LC/ESI‐MS

Abstract

Original PaperQuantitation of imidazo[1,2-a]quinoxaline derivatives in human and rat plasma using LC/ESI-MS Since several years, our group developed quinoxalinic compounds. Among the synthesized compounds, in the imidazo[1,2-a]quinoxaline series, EAPB0203 has shown interesting activities both on melanoma and lymphoma. The structure of EAPB0203 has been modulated and a new compound, EAPB0503, exhibits an in vitro cytotoxic activity on melanoma cancer cell line 7 -9 times higher than EAPB0203. We validated an LC/ESI-MS method to simultaneously quantify EAPB0503 and its metabolite EAPB0603 in human and rat plasma. Chromatography was performed on a C8 Zorbax eclipse XDB column with a mobile phase consisting of acetronitrile and formate buffer gradient elution. LC-MS data were acquired in SIM mode at m/z 305, 291, and 303 for EAPB0503, EAPB0603, and the internal standard, respectively. The drug/ internal standard peak area ratios were linked via quadratic relationships to concentrations (low range: 5 -300 lg/L, high range: 100 -1000 lg/L). The method is precise (precision, f14%) and accurate (recovery, 92 -113%). Mean extraction efficiencies, A72% for each analyte, were obtained. The lower LOQs were 5 lg/L. This highly specific and sensitive method was successfully used to investigate plasma concentrations of EAPB0503 and EAPB0603 in a pharmacokinetic study carried out in rat and would also be useful in clinical trials at a later stage.Keywords: Human and rat matrices / Imidazo[1,2-a]quinoxaline / LC/ESI-MS / Lymphoma / Melanoma /

Imidazoquinoxaline anticancer derivatives and imiquimod interact with tubulin: Characterization of molecular microtubule inhibiting mechanisms in correlation with cytotoxicity

“…Interestingly, sub-acute toxicity studies in Sprague Dawley rats receiving intravenous EAPB0203 at 5 mg/kg once daily or EAPB0503 at 3 mg/kg for five consecutive days showed no effect on vital organs nor on blood components [ 17 ]. Pharmacokinetic properties and metabolism of EAPB0203 and EAPB0503 have been extensively studied.…”

Lipid nanocapsules formulation and cellular activities evaluation of a promising anticancer agent: EAPB0503

“…Second, the saturation solubility of EAPB0503 in solvents was determined by HPLC. [ 24 25 ] Solvents were saturated with EAPB0503 and then centrifuged at 5000 g for 5 min using a Sigma 2k 25 ultracentrifuge (Sigma Zentrifugen, GmbH, Germany). The supernatant was assayed by HPLC with a LC62010HT (Shimadzu, Kyoto, Japan) using a C8 Zorbax® eclipse XDB (Extra-Dense Bonding) analytical column (150 mm × 4.6 mm, 5 μm, Agilent Technologies, Santa Clara, California, USA).…”

Characterization of a New Anticancer Agent, EAPB0203, and Its Main Metabolites: Nuclear Magnetic Resonance and Liquid Chromatography–Mass Spectrometry Studies

“…Among them, EAPB0203 and EAPB0503, belonging to the imidazo[1,2-a]quinoxaline series, have emerged as the most promising drugs with interesting antitumoral activities against melanoma, Tlymphoma, colon and breast cancer cell lines. [3][4][5][6][7][8] In a mice melanoma model, EAPB0203 was more potent than fotemustine. 3,7 Some data are now available on the pharmacokinetics of these compounds.…”

“…These compounds are analogues of imiquimod, the first member of the imidazoquinoline family, efficacious as a topical therapy for certain types of skin cancers. , The cytotoxic activity of these new compounds has been evaluated, in vitro, against human cancer cell lines. Among them, EAPB0203 and EAPB0503, belonging to the imidazo[1,2- a ]quinoxaline series, have emerged as the most promising drugs with interesting antitumoral activities against melanoma, T-lymphoma, colon, and breast cancer cell lines. − In a mice melanoma model, EAPB0203 was more potent than fotemustine. , Some data are now available on the pharmacokinetics of these compounds. , …”