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.
In the proximal tubules of rat (r) kidney, the polyspecific organic cation transporters (OCTs), rOCT1 and rOCT2, mediate the baso-lateral 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.
Matsuzaki
Takanobu
T
Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Morisaki
Takafumi
T
Sugimoto
Wakako
W
Yokoo
Koji
K
Sato
Daisuke
D
Nonoguchi
Hiroshi
H
Tomita
Kimio
K
Terada
Tomohiro
T
Inui
Ken-ichi
K
Hamada
Akinobu
A
Saito
Hideyuki
H
D000208:Acute Disease; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D015738:Famotidine / Q000493:pharmacokinetics; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*
D017920:Antiporters; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C100590:Slc22a2 protein, rat; C515734:Slc47a1 protein, rat; D015738:Famotidine