Relationship between in vitro transendothelial permeability and in vivo single-pass brain extraction.
In vitro transendothelial permeability was compared to in vivo rat single-pass cerebral extractions to evaluate which method would best estimate the blood-brain barrier (BBB) permeability of several SPECT imaging agents.


METHODS
Six 99mTc complexes and seven non-Tc complexes were tested in vitro using monolayers of primary bovine brain microvessel endothelial cells and in vivo using the rat single-pass cerebral extraction model. In vitro transendothelial permeability indices (PI) were determined by measuring the average percent of radioactivity traversing the monolayers as a function of time. In vivo single-pass cerebral extractions were determined using an indicator fractionation method.


RESULTS
A positive correlation between extraction and PI was found for the non-Tc complexes (r2 = 0.96). The CBF imaging agents 99mTc-ECD and 99mTc-PnAO have high values for E and PI, demonstrating that these agents penetrate the BBB and have a high membrane permeability, while the heart imaging agent 99mTc-sestamibi had low values for both E and PI. The low PI and E values for 99mTc-sestamibi are consistent with a low brain uptake for this agent, except in cases of disruption of the BBB. In contrast to 99mTc-ECD, 99mTc-PnAO and 99mTc-sestamibi, which had concordant values for E and PI, two highly lipophilic boronic acid adducts of technetium dioxime (BATOs), 99mTc-teboroxime and 99mTcCl(DMG)3(2)MP, had low negative values for PI, but high values for E. In addition, after 3 hr of incubation, the monolayer-to-medium concentration ratio of the BATOs was 642:1 and 744:1, respectively. This compares with values of 89:1 (99mTc-PnAO), 25:1 (99mTc-ECD) and 34:1 (99mTc-sestamibi).


CONCLUSIONS
These data suggest that the high in vivo single-pass extraction of the BATOs may be explained by a hydrophobic interaction with the luminal surface of the capillary endothelial cell plasma membrane. We conclude that a high single-pass extraction cannot necessarily be used to infer high BBB or membrane permeability.
Pirro
J P
JP
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Di Rocco
R J
RJ
Narra
R K
RK
Nunn
A D
AD
D000537:Aluminum Oxide; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D002199:Capillary Permeability; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D002417:Cattle; D002478:Cells, Cultured; D046508:Culture Techniques / Q000295:instrumentation; D004730:Endothelium, Vascular / Q000378:metabolism*; D008954:Models, Biological; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D014316:Tritium / Q000494:pharmacology; D014867:Water / Q000494:pharmacology
D002250:Carbon Radioisotopes; D015609:Organotechnetium Compounds; D014867:Water; D014316:Tritium; C033961:tritium oxide; D000537:Aluminum Oxide