Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography

Ørntoft, Nikolaj Worm; Munk, Ole Lajord; Frisch, Kim; Ott, Peter; Keiding, Susanne; Sørensen, Michael

doi:10.1016/j.jhep.2017.02.023

Cited by 42 publications

(58 citation statements)

References 26 publications

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“…Therefore, modeling approaches either have to rely on image-derived portal blood curves, which may be prone to imaging artefacts due to the small size of the investigated structures, or on data acquired in preclinical species (e.g. pigs) in which portal blood can be sampled (Ørntoft et al, 2017;Sørensen et al, 2016). Figure 3 shows a kinetic model used for quantification of hepatic disposition of the radiolabeled bile acid [ 11 C]cholylsarcosine in humans (Ørntoft et al, 2017).…”

Section: Modeling Transporter Function In Vivomentioning

confidence: 99%

Imaging techniques to study drug transporter function in vivo

Tournier

Stieger

Langer

2018

Pharmacology & Therapeutics

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Transporter systems involved in the permeation of drugs and solutes across biological membranes are recognized as key determinants of pharmacokinetics. Typically, the action of membrane transporters on drug exposure to tissues in living organisms is inferred from invasive procedures, which cannot be applied in humans. In recent years, imaging methods have greatly progressed in terms of instruments, synthesis of novel imaging probes as well as tools for data analysis. Imaging allows pharmacokinetic parameters in different tissues and organs to be obtained in a non-invasive or minimally invasive way. The aim of this overview is to summarize the current status in the field of molecular imaging of drug transporters. The overview is focused on human studies, both for the characterization of transport systems for imaging agents as well as for the determination of drug pharmacokinetics, and makes reference to animal studies where necessary. We conclude that despite certain methodological limitations, imaging has a great potential to study transporters at work in humans and that imaging will become an important tool, not only in drug development but also in medicine. Imaging allows the mechanistic aspects of transport proteins to be studied, as well as elucidating the influence of genetic background, pathophysiological states and drug-drug interactions on the function of transporters involved in the disposition of drugs.

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Section: Modeling Transporter Function In Vivomentioning

confidence: 99%

Imaging techniques to study drug transporter function in vivo

Tournier

Stieger

Langer

2018

Pharmacology & Therapeutics

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“…In later studies, [ 11 C]cholylsarcosine PET was applied in human healthy volunteers as well as in patients with cholestatic liver disease [89,90]. Reduced biliary secretion was found in patients with cholestatic liver disease, supporting that radiolabeled bile salt derivatives can be used to quantify changes in hepatobiliary transporter activity caused by disease [89]. In addition, a 18 F-labeled analogue of cholylglycine, i.e.…”

Section: Measuring the Activity Of Bile Acid Transporters With Petmentioning

confidence: 96%

“…Pioneering work has been done with [ 11 C]cholylsarcosine, the N-[ 11 C]methyl analogue of the endogenous bile acid conjugate cholylglycine, which was used to visualize and quantify the in vivo kinetics of hepatobiliary secretion of bile acids in pigs [87,88]. In later studies, [ 11 C]cholylsarcosine PET was applied in human healthy volunteers as well as in patients with cholestatic liver disease [89,90]. Reduced biliary secretion was found in patients with cholestatic liver disease, supporting that radiolabeled bile salt derivatives can be used to quantify changes in hepatobiliary transporter activity caused by disease [89].…”

Section: Measuring the Activity Of Bile Acid Transporters With Petmentioning

confidence: 99%

“…However, other studies showed that a dual blood input function, including the radiotracer input from both vessels, is needed to obtain unbiased kinetic parameter estimates and that the use of solely an arterial input underestimates the rapid blood-tissue exchange [143]. Since the blood from the portal vein cannot be sampled in humans and its TAC is not easily derived from the PET images, some pharmacokinetic models have adopted a mathematical approach to consider the blood input from both, the hepatic artery and the portal vein [88,89]. This approach, which was validated in pigs (from which the portal vein blood can be sampled), mathematically estimates the portal vein TAC mainly from the sampled arterial blood and a parameter (β), which describes the mean transit time of the radiotracer from the intestinal arteries to the portal vein [141].…”

Section: Quantitative Analysis Of Imaging Data To Assess Hepatic Tranmentioning

confidence: 99%

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Use of imaging to assess the activity of hepatic transporters

Hernández-Lozano

Langer

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available. Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach. Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs. ARTICLE HISTORY

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“…Several of these (Table 2) are carbon-11 versions of small molecule drugs or drug metabolites which are known liver transporter substrates (e.g., erlotinib [49]; metformin [50], rosuvastatin [51], dehydropravastatin [52], telmisartan [53], and celecoxib metabolite [54]). 11 C-labeled bile acid derivatives have also been synthesised, such as [ 11 C]cholylsarcosine [55][56][57]; these have been used to investigate the kinetics of hepatobiliary tracer uptake and secretion in healthy pigs and humans in vivo, and to quantify perturbations that occur in patients with cholestasis.…”

Section: Petmentioning

confidence: 99%

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

Kenna

Waterton

Baudy

et al. 2018

Methods in Pharmacology and Toxicology

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Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

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Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography

Cited by 42 publications

References 26 publications

Imaging techniques to study drug transporter function in vivo

Imaging techniques to study drug transporter function in vivo

Use of imaging to assess the activity of hepatic transporters

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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