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.
Uppsala Imanet, GE Healthcare, P.O. Box 967, SE-751 85 Uppsala, Sweden. Stina.Syvanen@uppsala.imanet.se
Stina
S
Syvänen
Julien
J
Barletta
Gunnar
G
Blomquist
Bengt
B
Långström
Mats
M
Bergström
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