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 logD was the main determinant of the variability in V_ss, λ_z, and CL of the studied compounds. Moreover, λ_z and CL depended on LUMO and HEFO, while for V_z COAR was the only explanatory variable. The developed QSPKR models accounted for most of the variation in V_ss, λ_z, CL, and fraction unbound (f_u) (R² ranged from 0.68 to 0.91). Cross-validation confirmed the predictive ability of the models (Q² = 0.60, 0.71, 0.34, and 0.32 for V_ss, λ_z, CL, and f_u, respectively).

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