Previous studies have demonstrated the feasibility of 11C-erlotinib PET imaging in healthy volunteers , which may be combined with rifampicin administration . Discussion PET imaging is an appealing strategy to study the impact of OATP transporters on the tissue distribution of radiolabeled drugs . In vitro studies using transfected cells showed that erlotinib is specifically transported by the human OATP2B1 . Recent PET studies have demonstrated saturable liver uptake of 11C-erlotinib in humans . To the best of our knowledge, the transport of erlotinib by the rodent rOATP2B1 has not been addressed but a similar saturation of the liver uptake of 11C-erlotinib was also observed in mice . We therefore hypothesized that OATP inhibition with rifampicin may decrease the liver uptake of 11C-erlotinib with consequences for drug exposure to the lungs, as the therapeutic target tissue of erlotinib. OATP transporters are recognized as the key determinants for the PK of many drugs . They are expressed in the sinusoidal membrane of hepatocytes and were shown to control the uptake of their substrates from the blood into the liver. Conventional PK studies, based on the determination of drug concentrations in the plasma, have shown how alterations in hepatic OATP1B1 and OATP1B3 function may influence the plasma PK of diverse drugs. Genetic polymorphisms of the genes  as well as DDIs involving inhibitors of OATP transporters  have been deemed Rabbit Polyclonal to ACK1 (phospho-Tyr284) of clinical importance for PK variability. The importance of OATP2B1 in the liver is less understood, probably due to its overlapping substrate specificity with OATP1B1 and OATP1B3 . Expression of OATP2B1 has been detected at many other blood-tissue interfaces than the sinusoidal membrane of hepatocytes, suggesting that OATP2B1 may control the target/vulnerable tissue exposure to its substrates in addition to its impact on hepatobiliary clearance . Rifampicin is a prototypical OATP inhibitor used in clinical studies in drug development to assess the PK importance of OATP function [11, 26]. In vitro, rifampicin is a potent inhibitor of the human OATP1B1 (IC50?=?1.9??0.16?M) and OATP1B3 (IC50?=?6.4??0.5?M) and a weaker inhibitor of OATP2B1 (IC50?=?91.0??14.6?M) [27, 28]. Rifampicin was also shown to inhibit several rat OATPs including the liver-specific rOATP1B2 ( em K /em i?=?0.79?M). Rifampicin also inhibits rOATP1A1 ( em K /em i?=?18?M) and rOATP1A4 ( em K /em i?=?1.4C2.9?M) [29C31]. The inhibition potency of rifampicin for other SLC transporters of PK importance has been studied in vitro and suggests a relatively good specificity for OATP transporters. ID 8 Indeed, rifampicin inhibited neither organic cation transporter 1 (OCT1, em SLC22A1 /em , em K /em i? ?100?M) nor organic anion transporter 2 (OAT2, em SLC22A7 /em ), which are both expressed in the sinusoidal hepatocyte membrane. Rifampicin most likely does not inhibit organic cation transporter 2 (OCT2, em SLC22A2 /em ) and organic anion transporter 3 (OAT3, em SLC22A8 /em ) function ID 8 in vivo . Plasma concentrations of rifampicin, when administered to rats at a dose of 40?mg/kg i.v., ranged from 100 to 300?M, which exceeded the reported in vitro em K /em i values for inhibition of OATP transporters [20, 22]. The selected rifampicin dose was previously shown to inhibit the rOATP-mediated liver uptake of 11C-dehydropravastatin and 11C-rosuvastatin, as assessed with PET imaging in rats [20, 22]. In our study, we chose a simple i.v. bolus administration protocol, which did not require constant infusion during PET scanning. Our PET data showed a predominant liver accumulation of radioactivity, which was consistent with hepatobiliary elimination of erlotinib . A high hepatic accumulation of 11C-erlotinib has also been observed in mice and in humans [14, 15]. Rifampicin pretreatment significantly decreased the liver uptake and subsequent liver exposure to 11C-erlotinib. This suggested a role of sinusoidal rOATP transporters in ID 8 controlling the hepatobiliary elimination of erlotinib. Radioactivity in the liver, analyzed at 15?min after injection, mainly consisted of unmetabolized 11C-erlotinib, regardless of the presence or absence of rOATP inhibition. This suggested that the quantification of em k /em uptake, liver values was not influenced by radiotracer metabolism and accurately reflected the transfer constant of parent 11C-erlotinib from the blood into the liver. Rifampicin is also a potent inhibitor of MRP2 ( em ABCC2 /em ) expressed at the canalicular side of hepatocytes . Erlotinib is not a substrate of MRP2 . Consistently, the slopes.