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

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.

Positron Emission Tomography Imaging of [11C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A

“…On average, CsA did not affect CL s,efflux , although it showed a dramatic increase in two subjects and a modest decrease in the other two. The reason for this is not known but such increase in CL s,efflux has been observed with other OATP substrates . CL h (in the absence of CsA; see Eq.…”

Imaging techniques to study drug transporter function in vivo

“…[ 11 C]erlotinib was found to be transported in vitro at low concentrations as used for PET imaging by OATP2B1, but not by OATP1B1 and OATP1B3, whereas OATP2B1 transport was saturated at pharmacologic erlotinib concentrations. In vivo, liver uptake of [ 11 C]erlotinib was markedly lower after pre-treatment of healthy volunteers with a therapeutic erlotinib dose as compared with administration of a microdose of [ 11 C]erlotinib, which appeared to be caused by saturation of OATP2B1 transport (Bauer et al, 2017b) (Fig. 6).…”

“…When drugs are amenable to radiolabeling, it is now possible to investigate the interplay of membrane transporters in controlling the clearance and tissue distribution of drugs. Using this approach, the impact of SLC and ABC transporters has been revealed in a dynamic fashion for glyburide (Tournier et al, 2013), metformin , sulpiride (Takano et al, 2017), metoclopramide (Pottier et al, 2016), ciprofloxacin (Wanek et al, 2016) and erlotinib (Bauer et al, 2017b;Traxl et al, 2015), to cite a few examples. This emerging approach is increasingly regarded as a means to elucidate the overall impact of membrane transporters on drug distribution to tissues in animals and humans (Giacomini et al, 2010).…”

A Proof-of-Concept Study to Inhibit ABCG2- and ABCB1-Mediated Efflux Transport at the Human Blood–Brain Barrier

“…Ten blood samples were collected at baseline and hourly for 8 h and at approximately 21 h after erlotinib intake. Plasma obtained from centrifuged blood samples was kept at 280°C until analysis of erlotinib concentrations, which was performed as previously described (21).…”

“…Radioactivity concentrations in blood and plasma aliquots were measured in a g-counter, which was cross-calibrated with the PET camera. Plasma samples collected at 3.5, 5, 10, 20, 30, 40, and 60 min after radiotracer injection were analyzed for radiolabeled metabolites of 11 C-erlotinib using a previously described solid-phase extraction procedure (21,22). In 6 subjects, metabolite data were available for only the 20-and 40-min time points.…”