title: Quantitative structure-activity study on human pharmacokinetic parameters of benzodiazepines using the graph theoretical approach.
abstract: The graph theoretical indices for a series of 13 benzodiazepines were calculated using a graph-path topological method. The total molecule, the ring fragments, and combinations of ring fragments were subjected to a quantitative structure-activity analysis using eight pharmacokinetic parameters. The metabolic clearance and the blood-to-plasma concentration ratios were most highly correlated with the graph theoretical indices, with R values of 0.975 and 0.938, respectively. These correlations were found when the diazepine + benzo fragment and phenyl fragment were used to calculate the graph-path indices. Terminal disposition half-life was correlated with the benzo + diazepine fragment, with R = 0.969. Truncating the graph-path codes by eliminating cycles in the total molecule markedly improved the correlation coefficients. When compared to the graph-path indices for the total molecule, the correlation coefficients for the terminal disposition half-life and metabolic clearance data rose from 0.721 to 0.935 and from 0.770 to 0.968, respectively, using the graph-path indices of the truncated molecule. Intrinsic clearance of unbound drug also was poorly correlated with the total molecule (r less than 0.7) but rose significantly using the graph-path indices of the truncated molecule (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively).
authors.affiliation: Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha 68105-1065.
authors.forename: R S
authors.initials: RS
authors.lastname: Markin
authors.forename: W J
authors.initials: WJ
authors.lastname: Murray
authors.forename: H
authors.initials: H
authors.lastname: Boxenbaum
mesh_terms: D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001569:Benzodiazepines; D006207:Half-Life; D006586:Hexanes; D006801:Humans; D008433:Mathematics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D006586:Hexanes; D001569:Benzodiazepines