Pharmacokinetics of P-glycoprotein inhibition in the rat blood-brain barrier.
This article describes the experimental set-up and pharmacokinetic modeling of P-glycoprotein function in the rat blood-brain barrier using [(11)C]verapamil as the substrate and cyclosporin A as an inhibitor of P-gp. [(11)C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady-state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [(11)C]verapamil infusion. The brain uptake of [(11)C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [(11)C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA-induced P-gp inhibition. The brain pharmacokinetics of [(11)C]verapamil was well described by a two-compartment model. The effect of CsA on the uptake of [(11)C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [(11)C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 microg/mL (4.1 microM). The model parameters indicated that 93% of the outward transport of [(11)C]verapamil was P-gp mediated.
Syvänen
Stina
S
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden. stina.syvanen@uppsala.imanet.se
Hooker
Andrew
A
Rahman
Obaidur
O
Wilking
Helena
H
Blomquist
Gunnar
G
Långström
Bengt
B
Bergström
Mats
M
Hammarlund-Udenaes
Margareta
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D008297:Male; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D014700:Verapamil