Document Detail


Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells.
MedLine Citation:
PMID:  16928358     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Takeshi Hirano; Satoru Yasuda; Yuki Osaka; Masaki Kobayashi; Shirou Itagaki; Ken Iseki
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Publication Detail:
Type:  Journal Article     Date:  2006-07-14
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1758     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-07     Completed Date:  2007-01-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1743-50     Citation Subset:  IM    
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.
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MeSH Terms
Descriptor/Qualifier:
Biological Transport, Active / drug effects*,  physiology
Caco-2 Cells
Carnitine / metabolism*
Dose-Response Relationship, Drug
Fluoroquinolones / pharmacology*
Humans
Hydrogen-Ion Concentration
Intestines / cytology,  metabolism
Kinetics
Leucovorin / pharmacology*
Membrane Proteins / analysis,  metabolism*
Organic Cation Transport Proteins / antagonists & inhibitors*
Piperazines / pharmacology*
Chemical
Reg. No./Substance:
0/Fluoroquinolones; 0/Membrane Proteins; 0/Organic Cation Transport Proteins; 0/Piperazines; 0/SLC22A5 protein, human; 119914-60-2/grepafloxacin; 541-15-1/Carnitine; 58-05-9/Leucovorin

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