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.

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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.

Layman's Abstract

In vitro experiments refer to the basic level of drug interaction studies, and are currently the means by which scientists identify and characterize the role of transporter proteins on drug absorption and elimination from different organs/tissues. The nature of these simple and isolated systems allows the study of transport mechanisms at the cellular level, which however do not reflect their overall effect in vivo, leading to under/over-estimations. Nevertheless, studying the behaviour of specific transporter systems with in vitro techniques provides detailed insights on the functionality of these transporters and further improves the prediction of the effect on in vivo situations and potential hazards such as DDIs.On the other hand, DCE-MRI techniques have experienced an enormous growth due to the rapidly emerging technologies (faster image acquisition, high spatial resolution). These advancements have the potential to improve diagnostic imaging procedures by providing a more quantitative approach and potentially allowing the study of tissue physiology with non-invasive techniques. Several studies have illustrated the potential of studying transporter-mediated processes using DCE-MRI techniques and its ability to identify DDIs, which are a major concept when it comes to drug development and medication.In this thesis, a series of in vitro and in vivo DCE-MRI experiments are presented, which demonstrate the potential of a translational approach to the investigation of transporter-mediated processes.

Keyword(s)

BCRP; Clinical; Contrast Agents; DCE-MRI; Drug drug interactions; Efflux; Gadoxetate; Hepatobiliary; In vitro; In vivo; LC-MS/MS; Liver Function; OATP; Pgp; Pharmacokinetics; Preclinical; Primovist; Tracer Kinetic Model; Uptake

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