Characterization of the physiological spaces and distribution of tolbutamide in the perfused rat pancreas.

摘要

PURPOSE: To set up and validate a viable perfused rat pancreas model suitable for pharmacokinetic studies. MATERIALS AND METHODS: We setup and conducted multiple indicator dilution studies in the single pass perfused rat pancreas. The distribution of the reference markers [99mTc]-red blood cells (RBC), [14C]-sucrose, and [3H]-water, and tolbutamide were analysed using both non-parametric and parametric methods. RESULTS: The perfusion preparation was observed to be viable by oxygen consumption, outflow perfusate pH, lactate release and insulin release in response to glucose. Parametric analysis of the outflow profiles suggested that the transport of water and tolbutamide from the vascular space was permeability limited. Parametric and nonparametric estimates of Vd for RBC and sucrose were similar and were 0.14+/-0.01, 0.15 0.005 and 0.35+/-0.01 ml/g. The parametric estimate for water, 1.04+/-0.05 ml/g was greater than the nonparametric estimate, 0.89+/-0.02 ml/g. The multiple indicator dilution method Vd of tolbutamide of 0.75+0.08 ml/g was similar to the reported value of 0.73+/-0.04 ml/g estimated by tissue partitioning studies. CONCLUSIONS: A viable single pass pancreas perfusion model was established and applied to define distribution spaces of reference markers and the distribution kinetics of tolbutamide.