title: Genetic deficiency of carnitine/organic cation transporter 2 (slc22a5) is associated with altered tissue distribution of its substrate pyrilamine in mice.
abstract: Carnitine/organic cation transporter 2 (OCTN2) recognizes various cationic compounds as substrates in vitro, but information on its pharmacokinetic role in vivo is quite limited. This paper demonstrates altered tissue distribution of the OCTN2 substrate pyrilamine in juvenile visceral steatosis (jvs) mice, which have a hereditary defect of the octn2 gene. At 30 min after intravenous injection of pyrilamine, the tissue-to-plasma concentration ratio (K(p)) in the heart and pancreas was higher, whereas the K(p) in kidney and testis was lower in jvs mice compared with wild-type mice. Pyrilamine transport studies in isolated heart slices confirmed higher accumulation, together with lower efflux, of pyrilamine in the heart of jvs mice. The higher accumulation in heart slices of jvs mice was abolished by lowering the temperature, by increasing the substrate concentration, and in the presence of other H(1) antagonists or another OCTN2 substrate, carnitine, suggesting that OCTN2 extrudes pyrilamine from heart tissue. On the other hand, the lower distribution to the kidney of jvs mice was probably due to down-regulation of a basolateral transporter coupled with OCTN2, because, in jvs mice, (i) the K(p) of pyrilamine in kidney assessed immediately after intravenous injection (approximately 1 min) was also lower, (ii) the urinary excretion of pyrilamine was lower, and (iii) the uptake of pyrilamine in kidney slices was lower. The renal uptake of pyrilamine was saturable (K(m) approximately 236 microM) and was strongly inhibited by cyproheptadine, astemizole, ebastine and terfenadine. The present study thus indicates that genetic deficiency of octn2 alters pyrilamine disposition tissue-dependently.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kato
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D015536:Down-Regulation; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D011738:Pyrilamine / Q000493:pharmacokinetics*; D000074058:Solute Carrier Family 22 Member 5; D013696:Temperature; D014018:Tissue Distribution
chemical_list: D006634:Histamine H1 Antagonists; D027701:Organic Cation Transport Proteins; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D011738:Pyrilamine