Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET

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Syvänen, StinaUppsala universitet,Institutionen för farmaceutisk biovetenskap (author)

Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET

Article/chapterEnglish2006

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Elsevier BV,2006
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LIBRIS-ID:oai:DiVA.org:uu-96870
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-96870URI
https://doi.org/10.1016/j.neuroimage.2006.05.047DOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [C-11]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [C-11]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [C-11]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [C-11]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [C-11]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [C-11]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmaceutiska vetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmaceutical Sciences hsv//eng
PET
["C]verapamil
p-glycoprotein
cyclosporin
pharmacokinetics
modeling
blood-brain barrier
active efflux
PHARMACY
FARMACI

Added entries (persons, corporate bodies, meetings, titles ...)

Blomquist, Gunnar (author)
Sprycha, Margareta (author)
Höglund, A. Urban (author)
Roman, Magnus (author)
Eriksson, Olof (author)
Hammarlund-Udenaes, MargaretaUppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)marghamm (author)
Långström, BengtUppsala universitet,Institutionen för biokemi och organisk kemi(Swepub:uu)benglang (author)
Bergström, MatsUppsala universitet,Institutionen för farmaceutisk biovetenskap (author)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

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In:NeuroImage: Elsevier BV32:3, s. 1134-11411053-81191095-9572

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

Articles in the publication: NeuroImage

By the university: Uppsala University

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