Effect of tyrosine kinase inhibitors on renal handling of creatinine by MATE1

Abstract

Creatinine is actively secreted across tubular epithelial cells via organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1). We previously showed that the tyrosine kinase inhibitor (TKI) crizotinib inhibits OCT2-mediated transport of creatinine. In the present work, we examined the inhibitory potency of TKIs, including crizotinib, on MATE1-mediated transport of creatinine. Then, we used the kinetic parameters estimated in this and the previous work to predict the potential impact of TKIs on serum creatinine level (SCr) via reversible inhibition of creatinine transport. Crizotinib inhibited [14C]creatinine uptake by MATE1-overexpressing cells, and the inhibitory effect increased with incubation time, being greater in the case of pre-incubation or combined pre-incubation/co-incubation (pre/co-incubation) than in the case of co-incubation alone. The inhibition was non-competitive, with Ki values of 2.34 μM, 0.455 μM and 0.342 μM under co-, pre- or pre/co-incubation conditions, respectively. Similar values were obtained for inhibition of [3H]MPP+ uptake by MATE1-overexpressing cells. Gefitinib, imatinib, pazopanib, sorafenib, and sunitinib also inhibited MATE1-mediated creatinine uptake. Further, all these TKIs except pazopanib inhibited [14C]creatinine uptake by OCT2-overexpressing cells. In rat kidney slices, the ratio of unbound tissue accumulation of TKIs to extracellular concentration ranged from 2.05 to 3.93. Prediction of the influence of TKIs on SCr based on the renal creatinine clearance and plasma maximum unbound concentrations of TKIs suggested that crizotinib and imatinib might increase SCr by more than 10% in the clinical context. Accordingly, it is necessary to be cautious in diagnosing TKI-induced renal failure only on the basis of an increase of SCr.

Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects

“…Elevated serum creatinine because of inhibition of creatinine tubular secretion has been observed with other kinase inhibitors indicated for the treatment of cancer in clinical 22,29 and preclinical 30 studies. In clinical trials of abemaciclib, a selective inhibitor of cyclin‐dependent kinases 4 and 6 indicated for the treatment of hormone‐receptor‐positive, HER2‐negative advanced or metastatic breast cancer, 31 reversible serum creatinine elevations of approximately 15% to 40% from baseline have been observed 22,32,33 .…”

<p>Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review</p>

“…Crizotinib inhibits the P-gp, OCT1/2, OATPB1/3, OATP2B1, OATP4C1, multidrug and toxin extrusion protein (MATE1), and MATE2-K, but not OAT1/3, or bile salt export pump transporter (BSEP). 11,12,49,50 Razaet al 51 reported that crizotinib significantly increased the sensitivity of P-gp over-expressing cells in response to doxorubicin and paclitaxel. Therefore, crizotinib may have the potential to increase the plasma concentrations of co-administered P-gp substrates, and close clinical surveillance is recommended when crizotinib is administered with these agents.…”

Changes of drug pharmacokinetics mediated by downregulation of kidney organic cation transporters Mate1 and Oct2 in a rat model of hyperuricemia

“…The uptake experiment was conducted as described previously [21]. HEK293/mock and HEK293/hMATE1 cells were plated at a density of 3.0 × 10 5 cells/well on 24-well plates and cultured for two days before an uptake assay.…”