### 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 < 0.7) but rose significantly using the graph-path indices of the truncated moleucle (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively.)

Original language | English (US) |
---|---|

Pages (from-to) | 201-208 |

Number of pages | 8 |

Journal | Pharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists |

Volume | 5 |

Issue number | 4 |

DOIs | |

State | Published - Jan 1 1988 |

### Fingerprint

### Keywords

- benzodiazepines
- pharmacokinetics
- quantitative structure–activity analysis (QSAR)
- topological approach

### ASJC Scopus subject areas

- Biotechnology
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
- Organic Chemistry
- Pharmacology (medical)

### Cite this

*Pharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists*,

*5*(4), 201-208. https://doi.org/10.1023/A:1015933527583

**Quantitative Structure–Activity Study on Human Pharmacokinetic Parameters of Benzodiazepines Using the Graph Theoretical Approach.** / Markin, Rodney Smith; Murray, W. J.; Boxenbaum, H.

Research output: Contribution to journal › Article

*Pharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists*, vol. 5, no. 4, pp. 201-208. https://doi.org/10.1023/A:1015933527583

}

TY - JOUR

T1 - Quantitative Structure–Activity Study on Human Pharmacokinetic Parameters of Benzodiazepines Using the Graph Theoretical Approach

AU - Markin, Rodney Smith

AU - Murray, W. J.

AU - Boxenbaum, H.

PY - 1988/1/1

Y1 - 1988/1/1

N2 - 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 < 0.7) but rose significantly using the graph-path indices of the truncated moleucle (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively.)

AB - 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 < 0.7) but rose significantly using the graph-path indices of the truncated moleucle (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively.)

KW - benzodiazepines

KW - pharmacokinetics

KW - quantitative structure–activity analysis (QSAR)

KW - topological approach

UR - http://www.scopus.com/inward/record.url?scp=0023933878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023933878&partnerID=8YFLogxK

U2 - 10.1023/A:1015933527583

DO - 10.1023/A:1015933527583

M3 - Article

VL - 5

SP - 201

EP - 208

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 4

ER -