Effect of cyclosporin A on the brain regional distribution of doxorubicin in rats.
Doxorubicin (DOX) is an anthracycline antibiotic that possesses broad-spectrum antineoplastic activity, and is one of the most important anticancer agents. The purpose of this study was to investigate the effects of cyclosporine A (CsA) on the brain regional distribution of DOX and its liposome DOX formulation (Lipo-Dox). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to measure DOX in rat plasma and in various brain regions (cerebral cortex, hippocampus, striatum, midbrain, cerebellum, and the rest of brain). Good linearity was achieved over the 5-5000ng/mL range, with coefficients of correlation greater than 0.995. The limit of quantification for doxorubicin was 5ng/mL. This study was divided into the following four groups: DOX alone, DOX+CsA, Lipo-Dox alone and Lipo-Dox+CsA. After administering DOX (5mg/kg, i.v.) alone and DOX+CsA (10mg/kg, i.v.), it was undetectable in various brain regions. When the same dose of Lipo-Dox (5mg/kg, i.v.) and Lipo-Dox+CsA (10mg/kg, i.v.) were given individually, the plasma level and the brain regional level of DOX were much greater than those of DOX given alone. These results indicate that Lipo-Dox prolongs the DOX level in plasma and enhances brain distribution of DOX. The disposition of DOX might be regulated by P-glycoprotein.
Hsieh
Yen-Ju
YJ
Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
Chang
Chih-Hsien
CH
Huang
Shu-Pei
SP
Lin
Chia-Wen
CW
Wang
Meng-Nan
MN
Wu
Yu-Tse
YT
Chen
Yu-Jen
YJ
Tsai
Tung-Hu
TH
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002853:Chromatography, Liquid; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
D004317:Doxorubicin; D016572:Cyclosporine