Effect of therapeutic moderate hypothermia on multi-drug resistance protein 1-mediated transepithelial transport of drugs.
To clarify the effect of therapeutic moderate hypothermia on drug distribution, transepithelial transport via multi-drug resistance protein 1 (MDR1) (also called P-glycoprotein or ABCB1) was evaluated at various temperatures in vitro using LLC-GA5-COL150 cells, which were established by transfecting human MDR1 complementary deoxyribonucleic acid into kidney epithelial LLC-PK(1) cells and express MDR1 on the apical membrane. MDR1 is expressed in the blood-brain barrier to limit drug distribution to the brain by exporting exogenous substances including calcium blockers and antiarrhythmic drugs. Digoxin was used as a typical substrate, as well as the non-substrate tetracycline and paracellular marker inulin. MDR1-mediated transport of digoxin decreased at lower temperatures. Transport of tetracycline also decreased at lower temperatures, probably due to changes in membrane fluidity. However, no change was found at over 32 degrees C, suggesting that passive diffusion does not change during moderate hypothermia. The distribution of MDR1 substrates should be considered during hypothermic conditions, as the clinical outcome could be affected.
Jin
Jiang-shu
JS
Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Sakaeda
Toshiyuki
T
Kakumoto
Mikio
M
Nishiguchi
Kohshi
K
Nakamura
Tsutomu
T
Okamura
Noboru
N
Okumura
Katsuhiko
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000889:Anti-Arrhythmia Agents; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D004848:Epithelium / Q000378:metabolism; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D011802:Quinidine / Q000493:pharmacokinetics*; D013752:Tetracycline / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D004077:Digoxin; D013752:Tetracycline; D011802:Quinidine