PET-evaluated transport of [11C]hydroxyurea across the rat blood-brain barrier--lack of influence of cyclosporin and probenecid.
The transport of hydroxyurea, a ribonucleoside reductase inhibitor, over biological membranes is slow and it has therefore been suggested that the substance could interact with an active efflux transporter. The transport of [(11)C]hydroxyurea into the rat brain was therefore studied after administration of the multidrug resistance protein inhibitor probenecid (50 and 150 mg/kg), the P-glycoprotein inhibitor cyclosporin A (25 mg/kg), hydroxyurea (50, 150 and 450 mg/kg) and mannitol (25%). None of the intervention drugs affected the brain uptake of [(11)C]hydroxyurea. The brain-to-plasma concentration ratios (K(p)), with or without intervention drug, were in the range 0.12-0.25 after 60 min of [(11)C]hydroxyurea infusion. [(11)C]Verapamil, a P-glycoprotein substrate with low brain penetration, was used to study the ability of hydroxyurea to inhibit P-glycoprotein. Administration of hydroxyurea (150 and 450 mg/kg) did not increase brain concentrations of [(11)C]verapamil. It is therefore unlikely that hydroxyurea is a substrate for or an inhibitor of P-glycoprotein or a substrate for a probenecid sensitive transport system. The low brain concentrations may instead be the result of slow uptake due to the hydrophilic nature of hydroxyurea.
Syvänen
Stina
S
Uppsala Imanet, GE Healthcare, P.O. Box 967, SE-751 85 Uppsala, Sweden. Stina.Syvanen@uppsala.imanet.se
Barletta
Julien
J
Blomquist
Gunnar
G
Långström
Bengt
B
Bergström
Mats
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006918:Hydroxyurea / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D008353:Mannitol; D016572:Cyclosporine; D014700:Verapamil; D011339:Probenecid; D006918:Hydroxyurea