Mechanisms by which 2',3'-dideoxyinosine (ddI) crosses the guinea-pig CNS barriers; relevance to HIV therapy.
The influence of transport mechanisms at the blood-brain barrier (BBB) and blood-CSF barrier (choroid plexus) on the CNS distribution of anti-human immunodeficiency virus (HIV) drugs was examined using guinea-pig brain perfusion and incubated choroid plexus models. 2',3'-dideoxyinosine (ddI) passage across the BBB was demonstrated to be via non-saturable (Kd = 0.22 +/- 0.3 microL/min/g) and saturable (Km = 20.1 +/- 15.0 microm, Vmax = 6.5 +/- 2.1 pmol/min/g) processes. Cross competition studies implicated an equilibrative nucleoside transporter in this influx. The brain distribution of ddI was unchanged in the presence of additional nucleoside reverse transcriptase inhibitors (NRTIs). ddI transport from blood into choroid plexus was demonstrated to involve an organic anion transporting polypeptide 2-like transporter. The NRTIs, abacavir, 3'-azido 3'-deoxythymidine and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, competed with ddI for transporter binding sites at the choroid plexus, altering the tissue concentration of ddI. This has clinical implications as the choroid plexus is a site of HIV replication, and suboptimal CNS concentrations of anti-HIV drugs could result in neurological complications. Furthermore, this may promote the selection of drug resistant variants of HIV within the CNS, which could re-infect the periphery and lead to HIV therapy failure. This study indicates that understanding drug interactions at the transporter level could prove valuable when selecting drug combinations to treat HIV within the CNS.
Gibbs
J E
JE
Centre for Neuroscience, Guy's King's and St Thomas' School of Biomedical Science, King's College London, Guy's Hospital Campus, London Bridge, London SE1 1UL, UK.
Jayabalan
P
P
Thomas
S A
SA
D015084:2,4-Dichlorophenoxyacetic Acid / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000032:analysis / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D001923:Brain Chemistry; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002250:Carbon Radioisotopes; D002490:Central Nervous System / Q000737:chemistry / Q000378:metabolism*; D002831:Choroid Plexus / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016049:Didanosine / Q000032:analysis / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D004077:Digoxin / Q000494:pharmacology; D006168:Guinea Pigs; D008353:Mannitol / Q000032:analysis / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D010477:Perfusion; D011339:Probenecid / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics; D014316:Tritium
D019380:Anti-HIV Agents; D002250:Carbon Radioisotopes; D033703:Nucleoside Transport Proteins; D018894:Reverse Transcriptase Inhibitors; D014316:Tritium; D015084:2,4-Dichlorophenoxyacetic Acid; D008353:Mannitol; D004077:Digoxin; D016049:Didanosine; D011339:Probenecid