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Pharmacokinetics of...
Pharmacokinetics of P-glycoprotein inhibition in the rat blood-brain barrier
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- Syvänen, Stina (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Hooker, Andrew (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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Rahman, Obaidur (författare)
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Wilking, Helena (författare)
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- Blomquist, Gunnar (författare)
- Uppsala universitet,Institutionen för onkologi, radiologi och klinisk immunologi
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- Långström, Bengt (författare)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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- Bergström, Mats (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Hammarlund-Udenaes, Margareta (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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(creator_code:org_t)
- Elsevier BV, 2008
- 2008
- Engelska.
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 97:12, s. 5386-5400
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- PET
- pharmacokinetics
- pharmacokinetic/pharmacodynamic models
- P-glycoprotein
- blood-brain barrier
- active transport
- drug interactions
- efflux pumps
- metabolism
- population pharmacokinetics/pharmacodynamics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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