Pharmacokinetics of P-glycoprotein inhibition in the rat blood-brain barrier
2008 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 12, 5386-5400 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2008. Vol. 97, no 12, 5386-5400 p.
PET, pharmacokinetics, pharmacokinetic/pharmacodynamic models, P-glycoprotein, blood-brain barrier, active transport, drug interactions, efflux pumps, metabolism, population pharmacokinetics/pharmacodynamics
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-96871DOI: 10.1002/jps.21359ISI: 000261313200030PubMedID: 18384156OAI: oai:DiVA.org:uu-96871DiVA: diva2:171598