Investigation of the mechanism of enhancement of central nervous system delivery of 2'-beta-fluoro-2',3'-dideoxyinosine via a blood-brain barrier adenosine deaminase-activated prodrug.
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'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA), a model ADA-activated prodrug of 2'-beta-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'-beta-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.
Johnson
Mark D
MD
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA.
Chen
Jian
J
Anderson
Bradley D
BD
D000243:Adenosine Deaminase / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D016049:Didanosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats
D000998:Antiviral Agents; D011355:Prodrugs; C083218:2'-fluoro-2',3'-dideoxyinosine; D000243:Adenosine Deaminase; D016049:Didanosine