Structure-related pharmacokinetics of xanthines after direct administration into the peritoneal cavity of rats

The pharmacokinetic characteristics, peritoneal permeability and hydrophobicity of three xanthine derivatives, theophylline, enprofylline and 1-methyl-3-propylxanthine (MPX), were investigated in rats. Isotonic saline (30 ml) containing xanthine (2.5, 5 and 10 mg/kg) and blue dextran (0.2%) was administered intraperitoneally. The pharmacokinetic parameters of these xanthines were estimated using concentration-time data obtained from the peritoneal cavity and systemic circulation. Disappearance of these xanthines from the peritoneum declined in almost a monoexponential 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 fluid in the peritoneal cavity and the effect of drug adsorption on the peritoneal membrane was minimal. The pharmacokinetics of MPX was dose-dependent, but that of theophylline and enprofylline was not. The fraction of the administered dose absorbed through the peritoneal cavity was 0.71, 0.85, 0.93 for theophylline, enprofylline and MPX, respectively. The peritoneal clearance was significantly different (p < 0.05) among the three xanthines by two-way analysis of variance, and a strong correlation was noted between their peritoneal clearance and hydrophobicity (r = 0.98, p < 0.01). These findings suggest that hydrophobicity is an important determinant in the peritoneal permeation of these xanthines.