The distribution of the anti-HIV drug, 2'3'-dideoxycytidine (ddC), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors.
The brain and CSF distribution of the HIV reverse transcriptase inhibitor, 2'3'-dideoxycytidine (ddC), was investigated by the in situ brain perfusion and isolated incubated choroid plexus methods in the guinea pig. Multiple-time brain perfusions indicated that the distribution of [3H]ddC to the brain and CSF was low and the unidirectional rate constant (K(in)) for the brain uptake of this nucleoside analogue (0.52 +/- 0.10 microL/min/g) was not significantly different to that for the vascular marker, [14C]mannitol (0.44 +/- 0.09 microL/min/g). The influence of unlabelled ddC, six organic anion transport inhibitors and 3'-azido 3'-deoxythymidine (AZT) on the CNS uptake of [3H]ddC was examined in situ and in vitro. ddC, probenecid and 2,4-dichlorophenoxyacetic acid altered the distribution of [3H]ddC into the brain and choroid plexuses, indicating that the limited distribution of [3H]ddC was a result of an organic anion efflux transporter, in addition to the low lipophilicity of this drug (octanol-saline partition coefficient, 0.047 +/- 0.001). The CNS distribution was also sensitive to p-aminohippurate and deltorphin II, but not digoxin, suggesting the involvement of organic anion transporters (OAT1/OAT3-like) and organic anion transporting polypeptides (OATP1/OATPA-like). AZT did not effect the accumulation of [3H]ddC, indicating that when these nucleoside analogues are used in anti-HIV combination therapy, the CNS distribution of ddC is unchanged.
Gibbs
J E
JE
Centre for Neuroscience, Guy's, King's and St Thomas' School of Biomedical Science, King's College London, UK.
Thomas
S A
SA
D015084:2,4-Dichlorophenoxyacetic Acid / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000502:physiology*; D002196:Capillaries / Q000378:metabolism; D002250:Carbon Radioisotopes; D002831:Choroid Plexus / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004234:Diuretics, Osmotic / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006540:Herbicides / Q000494:pharmacology; D008353:Mannitol / Q000493:pharmacokinetics; D000442:Octanols; D009842:Oligopeptides / Q000494:pharmacology; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D010477:Perfusion; D011339:Probenecid / Q000494:pharmacology; D012965:Sodium Chloride; D014316:Tritium; D014528:Uricosuric Agents / Q000494:pharmacology; D016047:Zalcitabine / Q000493:pharmacokinetics*; D015215:Zidovudine / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000494:pharmacology
D019380:Anti-HIV Agents; D002250:Carbon Radioisotopes; D004234:Diuretics, Osmotic; D006540:Herbicides; D000442:Octanols; D009842:Oligopeptides; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C421102:Slco1a1 protein, rat; D014528:Uricosuric Agents; C114338:organic anion transport protein 3; D014316:Tritium; C060209:deltorphin II, Ala(2)-; D015084:2,4-Dichlorophenoxyacetic Acid; D008353:Mannitol; D012965:Sodium Chloride; D015215:Zidovudine; D016047:Zalcitabine; D011339:Probenecid; D010130:p-Aminohippuric Acid