RT Journal Article
SR Electronic
T1 Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 191
OP 198
DO 10.1124/dmd.30.2.191
VO 30
IS 2
A1 Mark D. Johnson
A1 Jian Chen
A1 Bradley D. Anderson
YR 2002
UL http://dmd.aspetjournals.org/content/30/2/191.abstract
AB Enhanced central nervous system (CNS) delivery of certain poorly penetrating 2′,3′-dideoxynucleosides has been achieved by designing prodrugs that are substrates for enzymes, such as adenosine deaminase (ADA), that are present at high activities in brain tissue. In this study, the potential role of adenosine deaminase localized within the endothelial cells of the blood-brain barrier (BBB) in providing enhanced intracellular and CNS delivery of an ADA-activated prodrug is assessed in vitro using cell culture models of the BBB. The kinetics of uptake and bioconversion of 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA), a model ADA-activated prodrug of 2′-β-fluoro-2′,3′-dideoxyinosine, were determined in primary cultured bovine brain microvascular endothelial cells. Model-based simulations of CNS availability derived from in vitro estimates of parameters for simple passive diffusion and ADA-catalyzed deamination suggest that ADA that is localized within the BBB plays an important role in the conversion of F-ddA to 2′-β-fluoro-2′,3′-dideoxyinosine during its passage across the BBB. Consistent with in vivo observations, these simulations demonstrate that elevated levels of certain enzymes, such as ADA, in the brain microvascular endothelial cells of the BBB may be exploited in the design of brain-targeted prodrugs or drug-carrier conjugates, which brain tissue selectively converts. The American Society for Pharmacology and Experimental Therapeutics