Organic Cation Transporter 1 Is Responsible for Hepatocellular Uptake of the Tyrosine Kinase Inhibitor Pazopanib

Abstract

Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. To characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its i.v. administration. Among the inhibitors, TPeA largely reduced hepatic distribution and plasma clearance of pazopanib, whereas CsA showed only partial reduction. Pazopanib uptake by isolated mouse hepatocytes was similarly reduced by these inhibitors, suggesting that OCTs play a major role in the overall hepatic uptake of pazopanib in mice. In human embryonic kidney cell line HEK293 cells stably transfected with human OCT1, pazopanib uptake was significantly higher than that in vector-transfected cells. Moreover, pazopanib uptake by OCT1 became saturated and was inhibited by TPeA, but not by CsA, confirming that pazopanib is also a substrate of human OCT1. Importantly, OCT1-mediated uptake of a typical OCT1 substrate metformin was inhibited by pazopanib with an IC value of 0.253 M, indicating that pazopanib has the potential for clinically relevant inhibition of human OCT1. Finally, pazopanib was taken up by cryopreserved human pooled hepatocytes in a time-dependent manner, and this uptake was largely reduced by TPeA but only partially reduced by CsA. Thus, the present findings suggest that OCT1 is responsible for hepatocellular uptake of pazopanib.

Decreased Disposition of Anticancer Drugs Predominantly Eliminated via the Liver in Patients with Renal Failure

“…These TKIs may be transported into hepatocytes by these solute carriers. Our recent in vitro and in vivo experiments have revealed that pazopanib is a substrate of the human organic cation transporter 1 [53].…”

Drug-induced liver injury

“…Several tyrosine kinase 250 inhibitors (TKIs, which are small molecules used to treat various forms of cancer) are substrates 251 and/or inhibitors of OATPs. Pazopanib has a boxed warning for hepatotoxicity in the US FDA 252 label, but the mechanism of hepatotoxicity is not related to inhibition of OATP1B1 40 ; pazopanib 253 uptake is mediated by the organic cation transporter 1 (OCT1, encoded by SLC22A1) 41 . The FDA 254 provides further guidance on in vitro metabolism-mediated and transporter-mediated drug-255 drug interaction studies with investigational drugs 42 .…”

Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate, an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats

“…To evaluate the tissue distribution of OATP1B endogenous substrates, tissue-to-plasma concentration ratio (K p,tissue ) was calculated by dividing the amount of OATP1B endogenous substrates per gram of tissue by their plasma concentration at 2 h after RSV administration. 22 To perform renal ligation, fasted rats were anesthetized with isoflurane, and the renal vein and artery of bilateral kidneys were ligated with surgical thread (Natsume). After bilateral kidneys were resected, the abdominal muscle was sutured to close the wound.…”

“…Briefly, hepatocytes were pre-incubated for 10 min at 37 C with KH buffer, and then the buffer was changed to a dosing solution of pre-warmed KH buffer containing substrate (d-HDA) with or without inhibitors (PBD, RIF, and CsA), and in the presence of 10 mM fatty acid-free human serum albumin (HSA; Sigma-Aldrich, St. Louis, MO). 22,25 After 30 min, the dosing solution was immediately removed, and cells were rinsed three times with ice-cold KH buffer. Transport studies involving RSV and PTV were performed using the same methodology but without HSA, and the incubation duration was set at 2 min.…”