Influence of OATPs on Hepatic Disposition of Erlotinib Measured With Positron Emission Tomography

Martin Bauer, Akihiro Matsuda, Beatrix Wulkersdorfer, Cécile Philippe, Alexander Traxl, Csilla Özvegy-Laczka, Johann Stanek, Lukas Nics, Eva Maria Klebermass, Stefan Poschner, Walter Jäger, Izabel Patik, Éva Bakos, Gergely Szakács, Wolfgang Wadsak, Marcus Hacker, Markus Zeitlinger, Oliver Langer

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19 Citations (Scopus)

Abstract

To assess the hepatic disposition of erlotinib, we performed positron emission tomography (PET) scans with [11C]erlotinib in healthy volunteers without and with oral pretreatment with a therapeutic erlotinib dose (300 mg). Erlotinib pretreatment significantly decreased the liver exposure to [11C]erlotinib with a concomitant increase in blood exposure, pointing to the involvement of a carrier-mediated hepatic uptake mechanism. Using cell lines overexpressing human organic anion-transporting polypeptides (OATPs) 1B1, 1B3, or 2B1, we show that [11C]erlotinib is selectively transported by OATP2B1. Our data suggest that at PET microdoses hepatic uptake of [11C]erlotinib is mediated by OATP2B1, whereas at therapeutic doses OATP2B1 transport is saturated and hepatic uptake occurs mainly by passive diffusion. We propose that [11C]erlotinib may be used as a hepatic OATP2B1 probe substrate and erlotinib as an OATP2B1 inhibitor in clinical drug–drug interaction studies, allowing the contribution of OATP2B1 to the hepatic uptake of drugs to be revealed.

Original languageEnglish
Pages (from-to)139-147
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume104
Issue number1
DOIs
Publication statusPublished - Jul 2018

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Bauer, M., Matsuda, A., Wulkersdorfer, B., Philippe, C., Traxl, A., Özvegy-Laczka, C., Stanek, J., Nics, L., Klebermass, E. M., Poschner, S., Jäger, W., Patik, I., Bakos, É., Szakács, G., Wadsak, W., Hacker, M., Zeitlinger, M., & Langer, O. (2018). Influence of OATPs on Hepatic Disposition of Erlotinib Measured With Positron Emission Tomography. Clinical Pharmacology and Therapeutics, 104(1), 139-147. https://doi.org/10.1002/cpt.888