Kinetic Analysis of Cerebrovascular Transport Based on the Multiple Indicator Dilution Method

Abstract

The multiple indicator dilution method (MID) is one experimental technique for evaluating capillary transport parameters of highly permeable neuroreceptor ligands. This technique has been widely used for the determination of capillary permeability in various organs and was adapted for studies of the blood brain barrier in rat, dog and human. Recently, Hertz and Paulson found that the apparent extraction of various substances increases during the initial part of the dilution curves in human brain. This increase in the apparent extraction can be explained by heterogeneity of transit times through the cerebral microcirculation. It is also important to consider intravascular separation of the test and reference substances (the effect of plasma protein binding and red cell carriage) and the effect of recirculation. Due to the highly tortuous character of the brain microcirculation, a distributed model of vascular transit that assumes a well-mixed tissue compartment to analyze indicator dilution curves from brain was developed. MID experiments based on the heterogeneity of capillary transit time can be used to estimate the transcapillary fluxes (both influx and efflux processes) of a highly diffusable test compound in the brain of a single animal. This appoach is potentially usefull in the study of the transport processes of lipophilic drugs and receptor-ligands that rapidly permeate brain capillaries.