[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body

Organic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and...

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Published in:Biomedicine & pharmacotherapy 2022-12, Vol.156, p.113994-113994, Article 113994
Main Authors: Marie, Solène, Breuil, Louise, Chalampalakis, Zacharias, Becquemont, Laurent, Verstuyft, Céline, Lecoq, Anne-Lise, Caillé, Fabien, Gervais, Philippe, Lebon, Vincent, Comtat, Claude, Bottlaender, Michel, Tournier, Nicolas
Format: Article
Language:English
Subjects:
[11C]glyburide
Bioengineering
Hepatocyte
Life Sciences
Liver
PET
Pharmaceutical sciences
Pharmacokinetics
Positron emission tomography
Transporters
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Summary:Organic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and non-hepatic OATPs. Dynamic whole-body positron emission tomography (DWB-PET) with [11C]glyburide was performed in humans for determination of the importance of OATPs for liver uptake and WBPK. Seven healthy male subjects (24.7 ± 3.2 years) underwent [11C]glyburide PET scan with concomitant blood sampling. All subjects underwent baseline [11C]glyburide PET scan. Five subjects underwent a subsequent [11C]glyburide PET scan after infusion of the potent OATP inhibitor rifampicin (9 mg/kg i.v.). The transfer constant (kuptake) of [11C]glyburide from blood to the liver was estimated using the integration plot method. The tissue exposure of [11C]glyburide was described by the area under the time-activity curve (AUC) and corresponding tissue/blood ratio (AUCR). [11C]glyburide was barely metabolized in both the baseline and rifampicin conditions. Parent (unmetabolized) [11C]glyburide accounted for > 90 % of the plasma radioactivity. Excellent correlation was found between radioactive counting in arterial blood samples and in the image-derived input function, in both the baseline and rifampicin conditions (R2 = 97.9 %, p 
ISSN:0753-3322
1950-6007
DOI:10.1016/j.biopha.2022.113994