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.
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 (kuptake) 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 kuptake, liver (p < 0.001), causing a significant 27.3% decrease in liver exposure (p < 0.001). Moreover, a significant decrease in kuptake, kidney with a concomitant decrease in AUCkidney (− 30.4%, p < 0.001) were observed. Rifampicin neither affected kuptake, lung nor AUClung.
Our results suggest that 11C-erlotinib is an in vivo substrate of rOATP transporters expressed in the liver and possibly of rifampicin-inhibitable transporter(s) in the kidneys. Decreased 11C-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.