Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats

Autor: Dorra Amor, Sébastien Goutal, Solène Marie, Fabien Caillé, Martin Bauer, Oliver Langer, Sylvain Auvity, Nicolas Tournier
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: EJNMMI Research, Vol 8, Iss 1, Pp 1-10 (2018)
Druh dokumentu: article
ISSN: 2191-219X
DOI: 10.1186/s13550-018-0434-0
Popis: Abstract Background Erlotinib is an epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor approved for treatment of non-small cell lung cancer. The wide inter-individual pharmacokinetic (PK) variability of erlotinib may impact treatment outcome and/or toxicity. Recent in vivo studies reported a nonlinear uptake transport of erlotinib into the liver, suggesting carrier-mediated system(s) to mediate its hepatobiliary clearance. Erlotinib has been identified in vitro as a substrate of organic anion-transporting polypeptide (OATP) transporters which expression does not restrict to hepatocytes and may impact the tissue uptake of erlotinib in vivo. Results The impact of rifampicin (40 mg/kg), a potent OATP inhibitor, on the liver uptake and exposure to tissues of 11C-erlotinib was investigated in rats (4 animals per group) using positron emission tomography (PET) imaging. Tissue pharmacokinetics (PK) and corresponding exposure (area under the curve, AUC) were assessed in the liver, kidney cortex, abdominal aorta (blood pool) and the lungs. The plasma PK of parent 11C-erlotinib was also measured using arterial blood sampling to estimate the transfer rate constant (k uptake) of 11C-erlotinib from plasma into different tissues. PET images unveiled the predominant distribution of 11C-erlotinib-associated radioactivity to the liver, which gradually moved to the intestine, thus highlighting hepatobiliary clearance. 11C-erlotinib also accumulated in the kidney cortex. Rifampicin did not impact AUCaorta but reduced k uptake, liver (p
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