Altered Pharmacokinetics of Cationic Drugs Caused by Down-Regulation of Renal Rat Organic Cation Transporter 2 (Slc22a2) and Rat Multidrug and Toxin Extrusion 1 (Slc47a1) in Ischemia/Reperfusion-Induced Acute Kidney Injury

Abstract

ABSTRACT:In the proximal tubules of rat (r) kidney, the polyspecific organic cation transporters (OCTs), rOCT1 and rOCT2, mediate the basolateral uptake of various organic cations, including many drugs, toxins, and endogenous compounds, and the apical type of H ؉ / organic cation antiporter, rat multidrug and toxin extrusion 1 (rMATE1), mediate the efflux of organic cations. Renal clearances of H 2 receptor antagonists, including famotidine, were reported to be decreased in patients with kidney disease. Therefore, acute kidney injury (AKI) could influence renal excretion and disposition of organic cations accompanied by the regulation of organic cation transporters. The aim of this study was to investigate the pharmacokinetic alteration of cationic drugs and the expression of tubular organic cation transporters, rOCT1, rOCT2, and rMATE1, in ischemia/reperfusion (I/R)-induced AKI rats. I/R-induced AKI increased the plasma concentration of i.v. administrated famotidine, a substrate for rOCT1 and rOCT2, or tetraethylammonium (TEA), a substrate for rOCT1, rOCT2, and rMATE1. The areas under the plasma concentration curves for famotidine and TEA were 2-and 6-fold higher in I/R rats than in sham-operated rats, respectively. The accumulation of TEA into renal slices was significantly decreased, suggesting that organic cation transport activity at the basolateral membranes was reduced in I/R rat kidney. The protein expressions of basolateral rOCT2 and luminal rMATE1 were down-regulated in I/R rat kidneys. These data suggest that the urinary secretion of cationic drugs via epithelial organic cation transporters is decreased in AKI.

A PET Tracer for Renal Organic Cation Transporters, 11C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

“…Consistent with this, a recent study demonstrated that variants in the gene SLC22A2, encoding OCT2, are associated with phenotypes of net tubular creatinine secretion and end-stage renal failure (3). A downregulation of OCT2 was associated with an experimental acute renal failure in rats (4,5), indicating that OCT2 may play an important role in renal disease. It was recently demonstrated that OCT2 is important for renal metformin transport, and other cationic drugs may competitively inhibit the renal metformin transport (6).…”

Characterization of the Inhibitory Effects ofN-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

“…For example, renal secretion of TEA was reduced in both rats and mice with impeded OCT1/2 function (Jonker et al, 2003;Matsuzaki et al, 2008). Likewise, plasma concentrations of metformin were increased in MATE1 knockout mice, and its urinary excretion was significantly reduced (Tsuda et al, 2009).…”

Characterization of the Disposition and Toxicokinetics ofN-Butylpyridinium Chloride in Male F-344 Rats and Female B6C3F1 Mice and Its Transport by Organic Cation Transporter 2

“…Therefore, impeded function of OCTs could alter the blood levels of these chemicals. It has been reported that TEA clearance was significantly decreased in the OCT1 and OCT2 double knockout mice and in the rats with lower OCT1 and OCT2 expression (Jonker et al, 2003;Matsuzaki et al, 2008). Absence of OCT2 has little effect on the pharmacokinetics of TEA in mice because both OCT1 and OCT2 are richly expressed in the mouse kidney, but OCT1 is weakly expressed in human kidney (Motohashi et al, 2002;Jonker et al, 2003).…”