STRUCTURE-RELATED PHARMACOKINETICS OF XANTHINES AFTER DIRECT ADMINISTRATION INTO THE PERITONEAL-CAVITY OF RATS

The pharmacokinetic characteristics, peritoneal permeability and hydro phobicity of three xanthine derivatives, theophylline, enprofylline an d 1-methyl-3-propylxanthine (MPX), were investigated in rats. Isotonic saline (30 ml) containing xanthine (2.5, 5 and 10 mg/kg) and blue dex tran (0.2%) was administered intraperitoneally. The pharmacokinetic pa rameters of these xanthines mere estimated using concentration-time da ta obtained from the peritoneal cavity and systemic circulation. Disap pearance of these xanthines from the peritoneum declined in almost a m onoexponential manner regardless of the dose administered. The volume of distribution (33.9 ml) in the peritoneal cavity was similar to the injection volume, indicating that dialysate was not diluted by the flu id in the peritoneal cavity and the effect of drug adsorption on the p eritoneal membrane was minimal. The pharmacokinetics of MPX was dose-d ependent, but that of theophylline and enprofylline was not. The fract ion of the administered dose absorbed through the peritoneal cavity wa s 0.71, 0.85, 0.93 for theophylline, enprofylline and MPX, respectivel y. The peritoneal clearance was significantly different (p < 0.05) amo ng the three xanthines by two-way analysis of variance, and a strong c orrelation was noted between their peritoneal clearance and hydrophobi city (r = 0.98, p < 0.01). These findings suggest that hydrophobicity is an important determinant in the peritoneal permeation of these xant hines.