Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood--brain barriers studied with (R)-[11C]verapamil positron emission tomography.

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Fältnamn	Indikatorer	Metadata
000		03599naa a2200385 4500
001		oai:DiVA.org:uu-185290
003		SwePub
008		121121s2012 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1852902 URI
024	7	a https://doi.org/10.1186/2191-219X-2-582 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Müllauer, Julia4 aut
245	1 0	a Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood--brain barriers studied with (R)-[11C]verapamil positron emission tomography.
264	1	c 2012
338		a electronic2 rdacarrier
520		a ABSTRACT: BACKGROUND: This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET). METHODS: Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood--brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated. RESULTS: Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment. CONCLUSIONS: Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Radiologi och bildbehandling0 (SwePub)302082 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Radiology, Nuclear Medicine and Medical Imaging0 (SwePub)302082 hsv//eng
700	1	a Kuntner, Claudia4 aut
700	1	a Bauer, Martin4 aut
700	1	a Bankstahl, Jens P4 aut
700	1	a Müller, Markus4 aut
700	1	a Voskuyl, Rob A4 aut
700	1	a Langer, Oliver4 aut
700	1	a Syvänen, Stinau Uppsala universitet,Geriatrik4 aut0 (Swepub:uu)stsyv838
710	2	a Uppsala universitetb Geriatrik4 org
773	0	t EJNMMI Researchg 2q 2x 2191-219X
856	4	u https://doi.org/10.1186/2191-219X-2-58y Fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:571164/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-185290
856	4 8	u https://doi.org/10.1186/2191-219X-2-58

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Av författaren/redakt...: Müllauer, Julia; Kuntner, Claudia; Bauer, Martin; Bankstahl, Jens ...; Müller, Markus; Voskuyl, Rob A; visa fler...; Langer, Oliver; Syvänen, Stina; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Radiologi och bi ...

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Av lärosätet: Uppsala universitet

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