title: Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice.
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 beta-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 K(m) of approximately 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.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakumamachi, Kanazawa 920-1192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kano
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Ito
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology; D002509:Cephaloridine / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D000074058:Solute Carrier Family 22 Member 5; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000890:Anti-Infective Agents; D001798:Blood Proteins; D027701:Organic Cation Transport Proteins; D018075:RNA, Complementary; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D002509:Cephaloridine; D002331:Carnitine