Hydroxyurea transport across the blood-brain and blood-cerebrospinal fluid barriers of the guinea-pig.
Hydroxyurea is used in the treatment of HIV infection in combination with nucleoside analogues, 2'3'-didehydro-3'deoxythymidine (D4T), 2'3'-dideoxyinosine or abacavir. It is distributed into human CSF and is transported from the CSF to sub-ependymal brain sites, but its movement into the brain directly from the blood has not been studied. This study addressed this by a brain perfusion technique in anaesthetized guinea-pigs. The carotid arteries were perfused with an artificial plasma containing [14C]hydroxyurea (1.6 microm) and a vascular marker, [3H]mannitol (4.6 nm). Brain uptake of [14C]hydroxyurea (8.0 +/- 0.9%) was greater than [3H]mannitol (2.4 +/- 0.2%; 20-min perfusion, n = 8). CSF uptake of [14C]hydroxyurea (5.6 +/- 1.5%) was also greater than [3H]mannitol (0.9 +/- 0.3%; n = 4). Brain uptake of [14C]hydroxyurea was increased by 200 microm hydroxyurea, 90 microm D4T, 350 microm probenecid, 25 microm digoxin, but not by 120 microm hydroxyurea, 16.5-50 microm D4T, 90 microm 2'3'-dideoxyinosine or 90 microm abacavir. [14C]Hydroxyurea distribution to the CSF, choroid plexus and pituitary gland remained unaffected by all these drugs. The metabolic half-life of hydroxyurea was > 15 h in brain and plasma. Results indicate that intact hydroxyurea can cross the brain barriers, but is removed from the brain by probenecid- and digoxin-sensitive transport mechanisms at the blood-brain barrier, which are also affected by D4T. These sensitivities implicate an organic anion transporter (probably organic anion transporting polypeptide 2) and possibly p-glycoprotein in the brain distribution of hydroxyurea and D4T.
Dogruel
M
M
Centre for Neuroscience Research, Guy's, King's and St. Thomas School of Biomedical Science, King's College London, London, UK.
Gibbs
J E
JE
Thomas
S A
SA
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology*; D002250:Carbon Radioisotopes; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000378:metabolism*; D002831:Choroid Plexus / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D006918:Hydroxyurea / Q000378:metabolism* / Q000493:pharmacokinetics*; D008353:Mannitol / Q000378:metabolism / Q000493:pharmacokinetics; D010477:Perfusion; D010902:Pituitary Gland / Q000737:chemistry / Q000378:metabolism; D018119:Stavudine / Q000494:pharmacology; D013687:Telencephalon / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D019380:Anti-HIV Agents; D002250:Carbon Radioisotopes; D014316:Tritium; D008353:Mannitol; D018119:Stavudine; D006918:Hydroxyurea