DRUG DISTRIBUTION STUDIES WITH MICRODIALYSIS .1. TISSUE DEPENDENT DIFFERENCE IN RECOVERY BETWEEN CAFFEINE AND THEOPHYLLINE

Microdialysis was applied to estimate concentrations of caffeine and theophylline in vitro or in vivo in blood, adipose tissue, muscle, liver and brain of rats. The in vivo and in vitro recovery of a compound was estimated by perfusing the dialysis probe with varying concentrations of caffeine and theophylline. The difference between the concentration in the dialysate and the concentration in the perfusion medium was plotted against the concentration in the perfusion medium and the slope of the resulting line was taken as an estimate of the recovery (difference method). In all experiments caffeine (20 mg/kg sc) and theophylline (20 mg/kg sc) were administered simultaneously. The recovery in vitro was virtually identical for caffeine and theophylline. The in vivo recovery of theophylline was significantly smaller than the recovery of caffeine in brain, liver, muscle and adipose tissue. The difference in recovery was significantly larger in the brain than in other tissues. The results show that the transport of a substance from the tissue to the dialysis probe may differ between tissues and between chemically very similar compounds. It is shown that the recovery of theophylline rapidly declines after death ensues which shows that energy-dependent processes are involved in the transport to the dialysis probe and not solely passive diffusion. It is suggested the differences in transport over brain capillaries explain the difference between caffeine and theophylline. It is concluded that the use of internal standards in microdialysis experiments requires validation in every specific application.