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

Abstract

BackgroundErlotinib 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.ResultsThe 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.ConclusionsOur 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.

Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats

“…RIF (40 mg/kg intravenously, i.v.) was injected immediately before [ 99m Tc]mebrofenin as previously described [ 33 ]. The PK of subcutaneously (s.c.) injected DTZ (20 mg/kg) has been reported in rats with plasma concentration > 10 µg/mL (25 µM) obtained 60 min after injection [ 34 ], consistent with the potency of DTZ to inhibit MRP2, assessed in vitro in the present study.…”

“…The uptake clearance of [ 99m Tc]mebrofenin from blood to the liver (CL uptake ) was estimated using the integration plot method [ 33 , 35 ] from 0 to 3 min (linear part) after [ 99m Tc]mebrofenin injection using the following equation: . X liver,t represents the total amount of [ 99m Tc]mebrofenin in the liver at the time t, C blood,t represents the concentration of [ 99m Tc]mebrofenin in the blood at time t (derived from the heart ROI).…”

Use of imaging to assess the activity of hepatic transporters

“…In mice and rats, rifampicin caused a pronounced reduction in the rate constant for the uptake of [ 11 C]erlotinib from the blood into the liver, while a similar, but markedly less pronounced decrease was observed in humans. These results indicated that rifampicin-inhibitable transporters, possibly OATP2B1 (SLCO2B1), contributed to the distribution of [ 11 C] erlotinib from the blood into the liver [97,98].…”

“…Several studies have addressed these questions by employing PET with radiolabeled drugs. Already marketed drugs, such as metformin, telmisartan, rosuvastatin, glyburide or erlotinib, have been studied with PET to assess their interactions with hepatocyte transporters and/or their vulnerability to transporter-mediated DDIs, in combination with prototypical transporter inhibitors [37,56,66,70,77,78,94,97,98]. This approach may potentially also find application in the study of new drug candidates to obtain crucial information on tissue distribution and transportermediated clearance, which may ultimately improve drug safety and efficacy.…”

Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib

“…Two control animals and two elacridar-treated animals were injected with 11 C-erlotinib. Arterial plasma sampling, sample preparation and analytical methods used for the determination of parent 11 C-erlotinib in plasma were performed as previously described [44]. Time activity curves (TACs) of unmetabolized parent 11 C-erlotinib in plasma were expressed as the percentage of injected dose per volume (%ID.mL −3 ) versus time.…”