title: Partitioning of 1,4-benzodiazepines into natural membranes.
abstract: The partition coefficients of several 1,4-benzodiazepin-2-ones (BZDs) were determined in a synaptosomal membrane-buffer system (Pm/b) by a two-component model analysis of the experimental data and the following values were obtained: flunitrazepam (FNTZ) = 32.2 +/- 1.5; diazepam (DZ) = 79 +/- 9; clonazepam (CNZ) = 30 +/- 4; nitrazepam (NTZ) = 38 +/- 2 and chlorodiazepoxide (CDZX) = 15.7 +/- 0.6. Correlations between these Pm/b and other chemical properties were performed by a principal component analysis. Hydrophobicity of BZDs, measured as the partition coefficients in different solvent systems, could be correlated with the presence of a methyl group at position 1 of the seven-member ring of the BZD molecule. The values of the partition coefficients of benzodiazepine in the synaptosomal membrane-buffer system were one order of magnitude lower than those obtained in an octanol-water or in ethyl acetate-water systems. The complexity of the membrane, unlike the isotropy of a pure solvent phase, provides a wide spectrum of types of interactions which, in turn, can be modulated in a dynamic manner by local or generalized changes in the lipid phase state. In that sense, the present values of Pm/b should be interpreted as an average tendency of BZDs to establish non-specific interactions with the molecules present in the different phases within biological membranes. Conversely, these Pm/b values reflect a consequence of the difference in complexity between natural membranes and the systems currently used as membrane models for drug partitioning.
authors.affiliation: Cátedra de Química Biológica, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Argentina.
authors.forename: M A
authors.initials: MA
authors.lastname: Perillo
authors.forename: D A
authors.initials: DA
authors.lastname: García
authors.forename: A
authors.initials: A
authors.lastname: Arce
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D002021:Buffers; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D007700:Kinetics; D011506:Proteins / Q000032:analysis / Q000737:chemistry; D013574:Synaptosomes / Q000648:ultrastructure
chemical_list: D002021:Buffers; D011506:Proteins; D001569:Benzodiazepines