An LC/MS quantitative and microdialysis method for cyclovirobuxine D pharmacokinetics in rat plasma and brain: The pharmacokinetic comparison of three different drug delivery routes.
To explore the brain-targeting of cyclovirobuxine D(CVB-D) after administered intranasally, the pharmacokinetics of CVB-D via three different drug delivery routes: intragastric (i.g.), intranasal (i.n.), and intravenous (i.v.) in rat brain and blood was compared. Firstly, an in vivo microdialysis method for sampling CVB-D in both plasma and brain of the rat was established. Secondly, a liquid chromatography-tandem mass spectrometry method has been developed and validated for determination of CVB-D in microdialysis samples. For plasma and brain microdialysis samples, liquid-liquid extraction was used and donepezil was chosen as internal standard. Both were followed by HPLC separation and positive electrospray ionization tandem mass spectrometry detection (ESI-MS/MS). Chromatographic separation was achieved on a agilent C18 column with a mobile phase of methanol-water (50:50, v/v) (pH 3.2) containing 0.1% formic acid and 5mM ammonium acetate. Mass spectrometric detection in the positive ion mode was carried out by selected reaction monitoring (MRM) of the transitions at m/z 403.4→372.3 for CVB-D and m/z 380.2→243.1 for donepezil (IS). Good linearities were obtained in the range of 10-4000ng/mL in rat microdialysates for CVB-D. The lowest limit of quantitation was 5ng/mL, with an extraction recovery >75%, and no significant matrix effects. Intra- and inter-day precisions were all <15% with accuracies of 97.26-116.20%. All of which proved that the established method was successfully applied to the pharmacokinetic study of CVB-D. Simultaneously, brain uptake and pharmacokinetic studies were performed by determination of CVB-D concentration in blood and brain respectively for CVB-D i.g., i.n. and i.v.. Results showed that the intranasal CVB-D could improve brain targeting and had advantages for direct nose to brain transport of CVB-D when compared with injection and oral delivery routes, which indicates that intranasal administration of CVB-D could be a promising approach for the treatment of cerebrovascular disease.
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guang dong 510006, China.
Jia-bao
JB
Wei
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guang dong 510006, China.
Qiao
Q
Lai
University of Florida, Gainesville, FL 32610, United States.
Stepan P
SP
Shumyak
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guang dong 510006, China.
Lan-fang
LF
Xu
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guang dong 510006, China.
Chen-xue
CX
Zhang
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guang dong 510006, China.
Jia-jun
JJ
Ling
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guang dong 510006, China. Electronic address: yuyang@gzucm.edu.cn.
Yang
Y
Yu
D000818:Animals; D001769:Blood; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004333:Drug Administration Routes; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D057230:Limit of Detection; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods*
D004365:Drugs, Chinese Herbal; C032939:cyclovirobuxine D
Different drug delivery routes; LC–MS/MS; Microdialysis; Rat brain and plasma pharmacokinetic