Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.686758
Title: DCE-MRI assessment of hepatic uptake and efflux of the contrast agent, gadoxetate, to monitor transporter-mediated processes and drug-drug interactions : in vitro and in vivo studies
Author: Georgiou, Leonidas
ISNI:       0000 0004 5919 9878
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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Abstract:
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques offer the opportunity to understand the physiological processes involved in the distribution of the contrast agent in vivo. This work utilises a liver specific contrast agent (gadoxetate) and demonstrates the potential use of these techniques to study transporter-mediated process in vivo. In vitro experiments investigated gadoxetate’s interaction with uptake and efflux transporters at the cellular level, ideally a prerequisite to understand the contribution of transporter proteins in in vivo pharmacokinetics. MRI was used to measure the accumulation of gadoxetate in fresh rat hepatocytes. Furthermore, LC-MS/MS methodology was optimised in conjunction with two in vitro systems to determine the role of transporters in gadoxetate uptake and efflux. HEK-OATP1B1 transfected cells were used to optimise the LC-MS/MS technique and Caco-2 cell monolayers were used to examine whether gadoxetate is a substrate of the efflux transporters, Pgp and BCRP. Subsequent studies demonstrated the use of DCE-MRI techniques to study transporter-mediated processes. Two pharmacokinetic models were proposed to quantify the uptake and efflux of gadoxetate in vivo. The suitability of the models in describing the liver concentration profiles of gadoxetate was assessed in pre-clinical and clinical reproducibility studies. Further pre-clinical experiments demonstrated the ability of the proposed DCE-MRI techniques to monitor changes in the uptake and efflux rate estimates of gadoxetate into hepatocytes, through co-administration of the transporter inhibitor, rifampicin, at two doses. The work presented demonstrates the potential use of DCE-MRI techniques as a diagnostic probe to assess transporter-mediated processes and drug-drug interactions (DDIs) in vivo.
Supervisor: Not available Sponsor: BBSRC ; AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.686758  DOI: Not available
Keywords: Gadoxetate ; Tracer Kinetic Model ; Pharmacokinetics ; Hepatobiliary ; Primovist ; DCE-MRI ; In vivo ; In vitro ; OATP ; Pgp ; BCRP ; Clinical ; Preclinical ; LC-MS/MS ; Liver Function ; Uptake ; Efflux ; Contrast Agents ; Drug drug interactions
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