Selection of experimental conditions for the accurate determination of blood--brain transfer constants from single-time experiments: a theoretical analysis

Abstract

Reliable blood-brain transfer constants can be determined from data obtained in single-time experiments (i.e., a single experimental time for tissue sampling). The accuracy of such measurements depends on factors such as the test molecule used and the experimental time chosen; therefore, the selection of optimal experimental conditions is important. In this presentation, a model of transport across the blood--brain barrier (BBB) was developed and used to determine appropriate experimental protocols for single-time experiments. Transfer numbers derived from published data with alpha-aminoisobutyric acid (AIB; a compound of low BBB permeability that is readily taken up by brain cells) and diethylenetriaminepentaacetic acid (DTPA; a compound of very low BBB permeability that is not taken up by brain cells) were inserted into the model and apparent blood-to-brain transfer constants (K1) were obtained. In addition, the two basic sets of transfer numbers were altered to mimic various experimental and pathological changes in blood--brain transport. The results of this analysis indicate that moderate to large transfer rates across the BBB (0.01-1.0 ml g-1 min-1) are more easily and reliably measured by AIB-like compounds. In contrast, compounds like DTPA are better test-molecules for measuring small changes in the BBB transfer rate (0.0001-0.001 ml g-1 min-1), provided an appropriate experimental time is chosen.