title: Metabolism and pharmacokinetics of EAPB0203 and EAPB0503, two imidazoquinoxaline compounds previously shown to have antitumoral activity on melanoma and T-lymphomas.
abstract: For several years, our group has been developing quinoxalinic compounds. Two of them, N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine (EAPB0203) and 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503), have emerged as the most promising anticancer drugs. In the present work, we determined metabolism pathways using liver microsomes from four mammalian species including human. We identified the cytochrome P450 isoform(s) involved in the metabolism and then investigated the pharmacokinetics and metabolism of EAPB0203 and EAPB0503 in rat after intravenous and intraperitoneal administration. Biotransformation of the compounds involved demethylation and hydroxylation reactions. Rat and dog metabolized the compounds at a higher rate than mouse and human. In all species, CYP1A1/2 and CYP3A isoforms were the predominant enzymes responsible for the metabolism. From human liver microsomes, unbound intrinsic clearances were approximately 56 ml/(min · g) protein. EAPB0203 and EAPB0503 were extensively bound to human plasma proteins, mainly human serum albumin (HSA) (∼98-99.5%). Thus, HSA could act as carrier of these compounds in human plasma. Scatchard plots showed patterns in which the plots yielded upwardly convex hyperbolic curves. On the basis of the Hill coefficients, there appears to be interaction between the binding sites of HSA, suggesting positive cooperativity. The main in vitro metabolites were identified in vivo. Total clearances of EAPB0203 and EAPB0503 [3.2 and 2.2 l/(h · kg), respectively] were notably lower than the typical cardiac plasma output in rat. The large volumes of distribution of these compounds (4.3 l/kg for EAPB0203 and 2.5 l/kg for EAPB0503) were consistent with extensive tissue binding. After intraperitoneal administration, bioavailability was 22.7% for EAPB0203 and 35% for EAPB0503 and a significant hepatic first-pass effect occurred.
authors.affiliation: Faculté de Pharmacie, Université Montpellier I, 15 Avenue Ch. Flahault, Montpellier Cedex 5, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Khier
authors.forename: Florence
authors.initials: F
authors.lastname: Gattacceca
authors.forename: Safia
authors.initials: S
authors.lastname: El Messaoudi
authors.forename: Florian
authors.initials: F
authors.lastname: Lafaille
authors.forename: Carine
authors.initials: C
authors.lastname: Deleuze-Masquéfa
authors.forename: Jacques
authors.initials: J
authors.lastname: Bompart
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cooper
authors.forename: Isabelle
authors.initials: I
authors.lastname: Solassol
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pinguet
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Bonnet
authors.forename: Françoise M M
authors.initials: FM
authors.lastname: Bressolle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; C528810:EAPB0203; C555838:EAPB0503; D011810:Quinoxalines