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Characterization of the Physiological Spaces and Distribution of Tolbutamide in the Perfused Rat Pancreas

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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 V d 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 V d 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.

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Abbreviations

BSA:

bovine serum albumin

MOPS:

3-[N-morpholino]propane-sulphonic acid

RBC:

red blood cells

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Acknowledgments

This work was financially supported by a grant from the National Health and Medical Research Council of Australia and a University of Queensland Development grant. Thanks goes to Anthony Phillips for invaluable training in surgical and perfusion methods, to Gihan Gunawardene for assistance in sample collection, and also to John Prins and Yuri Anissimov for helpful discdussion.

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  1. Department of Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, 4102, Australia

    Kent John Fanning & Michael S. Roberts

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  1. Kent John Fanning
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  2. Michael S. Roberts
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Correspondence to Michael S. Roberts.

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Fanning, K.J., Roberts, M.S. Characterization of the Physiological Spaces and Distribution of Tolbutamide in the Perfused Rat Pancreas. Pharm Res 24, 512–520 (2007). https://doi.org/10.1007/s11095-006-9167-2

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