title: Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells.
abstract: L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that L-carnitine exists as a zwitterion and that member of the OCTN family play an important role in its transport. The aims of this study were to characterize L-carnitine transport in the intestine by using Caco-2 cells and to elucidate the effects of levofloxacin (LVFX) and grepafloxacin (GPFX), which are zwitterionic drugs, on L-carnitine uptake. Kinetic analysis showed that the half-saturation Na+ concentration, Hill coefficient and Km value of L-carnitine uptake in Caco-2 cells were 10.3 +/- 4.5 mM, 1.09 and 8.0 +/- 1.0 microM, respectively, suggesting that OCTN2 mainly transports L-carnitine. LVFX and GPFX have two pKa values and the existence ratio of their zwitterionic forms is higher under a neutral condition than under an acidic condition. Experiments on the inhibitory effect of LVFX and GPFX on L-carnitine uptake showed that LVFX and GPFX inhibited L-carnitine uptake more strongly at pH 7.4 than at pH 5.5. It was concluded that the zwitterionic form of drugs plays an important role in inhibition of OCTN2 function.
authors.affiliation: Department of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.forename: Satoru
authors.initials: S
authors.lastname: Yasuda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Osaka
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Shirou
authors.initials: S
authors.lastname: Itagaki
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D001693:Biological Transport, Active / Q000187:drug effects* / Q000502:physiology; D018938:Caco-2 Cells; D002331:Carnitine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D007700:Kinetics; D002955:Leucovorin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology*; D000074058:Solute Carrier Family 22 Member 5
chemical_list: D024841:Fluoroquinolones; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; D010879:Piperazines; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; C075375:grepafloxacin; D002955:Leucovorin; D002331:Carnitine