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 μM) 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 μM hydroxyurea, 90 μM D4T, 350 μM probenecid, 25 μM digoxin, but not by 120 μM hydroxyurea, 16.5-50 μM D4T, 90 μM 2′3′ -dideoxyinosine or 90 μM 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.
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