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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  11 C-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  11 C-erlotinib was also measured using arterial blood sampling to estimate the transfer rate constant ( k  uptake ) of  11 C-erlotinib from plasma into different tissues.  PET images unveiled the predominant distribution of  11 C-erlotinib-associated radioactivity to the liver, which gradually moved to the intestine, thus highlighting hepatobiliary clearance.  11 C-erlotinib also accumulated in the kidney cortex. Rifampicin did not impact AUC aorta  but reduced  k  uptake, liver  ( p  < 0.001), causing a significant 27.3% decrease in liver exposure ( p  < 0.001). Moreover, a significant decrease in  k  uptake, kidney  with a concomitant decrease in AUC kidney  (− 30.4%,  p  < 0.001) were observed. Rifampicin neither affected  k  uptake, lung  nor AUC lung .    Conclusions  Our results suggest that  11 C-erlotinib is an in vivo substrate of rOATP transporters expressed in the liver and possibly of rifampicin-inhibitable transporter(s) in the kidneys. Decreased  11 C-erlotinib uptake by elimination organs did not translate into changes in systemic exposure and exposure to the lungs, which are a target tissue for erlotinib therapy.

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