Pharmacokinetics and Quantitative Structure-Pharmacokinetics Relationship Study of Xanthine Derivatives with Antidepressant, Anti-Inflammatory, and Analgesic Activity in Rats.

Objective: The aim of this study was to develop quantitative structure-pharmacokinetics relationship (QSPKR) models for a group of xanthine derivatives with proven pharmacological activity and to investigate its applicability for the prediction of the pharmacokinetics of these compounds.

Methods: The SYBYL-X, KowWin, and MarvinSketch programs were employed to generate a total of fourteen descriptor variables for a series of new compounds: 7- and 7,8-substituted theophylline derivatives (GR-1-GR-8) and three well-known methylxanthines. Pharmacokinetic profiles of all compounds were determined after intravenous administration of studied compounds to cannulated male rats. Pharmacokinetic parameters were calculated using noncompartmental analysis.

Results: Multiple linear regression revealed that log was the main determinant of the variability in , , and of the studied compounds. Moreover, and depended on LUMO and HEFO, while for COAR was the only explanatory variable. The developed QSPKR models accounted for most of the variation in , , , and fraction unbound () ( ranged from 0.68 to 0.91). Cross-validation confirmed the predictive ability of the models ( = 0.60, 0.71, 0.34, and 0.32 for , , , and f, respectively).

Conclusions: The multivariate QSPKR models developed in this study adequately predicted the overall pharmacokinetic behavior of xanthine derivatives in rats.