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Influence of OATPs on Hepatic Disposition of Erlotinib Measured With Positron Emission Tomography
Author(s) -
Bauer Martin,
Matsuda Akihiro,
Wulkersdorfer Beatrix,
Philippe Cécile,
Traxl Alexander,
ÖzvegyLaczka Csilla,
Stanek Johann,
Nics Lukas,
Klebermass EvaMaria,
Poschner Stefan,
Jäger Walter,
Patik Izabel,
Bakos Éva,
Szakács Gergely,
Wadsak Wolfgang,
Hacker Marcus,
Zeitlinger Markus,
Langer Oliver
Publication year - 2018
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.888
Subject(s) - erlotinib , pharmacology , medicine , positron emission tomography , drug interaction , organic anion transporter 1 , chemistry , drug , transporter , cancer , nuclear medicine , biochemistry , epidermal growth factor receptor , gene
To assess the hepatic disposition of erlotinib, we performed positron emission tomography (PET) scans with [ 11 C]erlotinib in healthy volunteers without and with oral pretreatment with a therapeutic erlotinib dose (300 mg). Erlotinib pretreatment significantly decreased the liver exposure to [ 11 C]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 [ 11 C]erlotinib is selectively transported by OATP2B1. Our data suggest that at PET microdoses hepatic uptake of [ 11 C]erlotinib is mediated by OATP2B1, whereas at therapeutic doses OATP2B1 transport is saturated and hepatic uptake occurs mainly by passive diffusion. We propose that [ 11 C]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.