Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice

Abstract

ABSTRACT:Carnitine/organic cation transporter (OCTN) 2 (SLC22A5) plays a pivotal role in renal tubular reabsorption of carnitine, a vitamin-like compound, on apical membranes of proximal tubules, but its role in relation to therapeutic drugs remains to be clarified. The purpose of the present study was to elucidate the involvement of OCTN2 in renal disposition of a ␤-lactam antibiotic, cephaloridine (CER), based on experiments with juvenile visceral steatosis (jvs) mice, which have a functional deficiency of the octn2 gene. Renal clearance of CER during constant intravenous infusion in wild-type mice was much higher than could be accounted for by glomerular filtration, but was decreased by increasing the infusion rate with minimal change in kidney-to-plasma concentration ratio, suggesting the existence of saturable transport mechanism(s) across the apical membranes. The plasma concentration profile and kidneyto-plasma concentration ratio after intravenous injection in jvs mice were higher than those in wild-type mice, whereas renal clearance in jvs mice was much lower than that in wild-type mice and could be accounted for by glomerular filtration. Uptake of CER by mouse OCTN2 was shown in Xenopus laevis oocytes expressing mouse OCTN2. The CER transport by OCTN2 exhibited saturation with K m of ϳ3 mM, which is similar to the renal CER concentration exhibiting saturation in renal clearance in vivo. The OCTN2-mediated CER transport was inhibited by carnitine and independent of Na ؉ replacement in the medium. These results show OCTN2 on apical membranes of proximal tubules plays a major role in renal secretion of CER in mice.

Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine

“…Animal and clinical studies suggest that these transporters mediate luminal efflux of drugs in the kidney. Juvenile visceral steatosis mice that exhibit systemic carnitine deficiency caused by a defect of Octn2 show a significant reduction in the renal clearance of TEA and cephaloridine accompanied by a significant increase in their kidney accumulation (Ohashi et al, 2001;Kano et al, 2009). In addition, a recent clinical study reported that healthy subjects homozygous for the L503F variant of OCTN1, which is associated with decreased OCTN1 function, exhibited smaller tubular secretion of gabapentin in the kidney compared with those homozygous for the reference allele (Urban et al, 2008).…”

Organic Anion and Cation Drug Transporters

“…The role of Octn2 in the drug disposition has also been reported in jvs mice, which showed altered disposition of pyrilamine and cephrolidine compared with normal mice (Kano et al, 2009;Kato et al, 2009a). The elimination of cephaloridine from the systemic circulation was significantly delayed, accompanied by its higher accumulation in the kidney compared with normal mice, suggesting that Octn2 mediates the luminal efflux of cephaloridine in addition to the reabsorption of carnitine (Kano et al, 2009).…”

“…The elimination of cephaloridine from the systemic circulation was significantly delayed, accompanied by its higher accumulation in the kidney compared with normal mice, suggesting that Octn2 mediates the luminal efflux of cephaloridine in addition to the reabsorption of carnitine (Kano et al, 2009). The role of Octn2 in the disposition of pyrimethamine appears to be complicated.…”

Xenobiotic transporters and kidney injury

“…More recently, mouse Octn2 was also shown to play a role in the apical uptake of cephaloridine. Experiments with juvenile visceral steatosis mice, which have a functional deficiency in the Octn2 gene, showed increased renal clearance of cephaloridine [251]. Furthermore, direct uptake of cephaloridine was shown in Xenopus laevis oocytes expressing mouse Octn2 (K m : 3 mM).…”