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

• Published in: Biomedicine & pharmacotherapy Vol. 156; p. 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: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.12.2022; Elsevier
• Subjects: [11C]glyburide; Bioengineering; Hepatocyte; Life Sciences; Liver; PET; Pharmaceutical sciences; Pharmacokinetics; Positron emission tomography; Transporters; Cliver,t; OCT; ABC; BBB; OAT; [11C]glyburide; Liver; DDI; SUVmax; SLC; DWB; AUC; kuptake; COVID-19; SD; Hepatocyte; Transporters; IDIF; HPLC; BCRP; UV; DILI; MRAC; P-gp; MR; SUR1; OATP; WBPK; VE; CT; VOI; Cblood,t; SUV; TAC; PK; fb; Pharmacokinetics; AUCR; Positron emission tomography; PET; [C]glyburide
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.113994

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 < 0.01). [11C]glyburide predominantly accumulated in the liver. Rifampicin decreased liver kuptake by 77.3 ± 7.3 %, which increased exposure in blood, kidneys, spleen, myocardium and brain (p < 0.05). No significant change in AUCR was observed except in the liver (p < 0.01). [11C]glyburide benefits from metabolic stability and high sensitivity to OATP inhibition which enables quantitative determination of OATP function. DWB-PET suggests negligible role for non-hepatic OATPs in controlling the tissue distribution of [11C]glyburide. [Display omitted] •Organic Anion-Transporting Polypeptides (OATP) form a family of influx transporters.•Importance of hepatic and non-hepatic OATP on drug delivery in humans is not known.•Whole-body PET imaging using the OATP substrate 11C-glyburide was performed in humans.•11C-glyburide benefits from unmet imaging properties to explore OATP function in humans.•PET data suggest a liver-selective importance of OATP in controlling drug delivery.