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 β-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 kidney-to-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 Km of ∼3 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.
Footnotes
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This work was supported by a grant-in-aid for scientific research provided by the Ministry of Education, Science, and Culture of Japan.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.025015.
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ABBREVIATIONS: OCTN2, carnitine/organic cation transporter 2; SCD, systemic carnitine deficiency; jvs, juvenile visceral steatosis; TEA, tetraethylammonium; CER, cephaloridine; OAT, organic anion transporter; CMD, cefamandole; CPM, cefpiramide; HPLC, high-performance liquid chromatography; CLtot, total clearance; CLrenal,p, renal clearance normalized by plasma concentration; CLrenal,k, renal clearance normalized by kidney concentration; I, infusion rate; Css,plasma, steady-state plasma concentration; Vss,urine, steady-state urinary excretion rate; Css,kidney, steady-state kidney concentration; CLsec, secretion clearance; Kp,kidney, kidney-to-plasma concentration ratio; GFR, glomerular filtration rate; AUC, area under the plasma concentration-time curve; Vdss, steady-state distribution volume; MRT, mean residence time; LC/MS/MS, liquid chromatography/tandem mass spectrometry.
- Received October 3, 2008.
- Accepted February 9, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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