Brain distribution of cetirizine enantiomers:: Comparison of three different tissue-to-plasma partition coefficients:: Kp, Kp,u, and Kp,uu
Brain distribution of cetirizine enantiomers:: Comparison of three different tissue-to-plasma partition coefficients:: Kp, Kp,u, and Kp,uu
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DOI：
10.1124/dmd.105.007211
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发表时间：
2006-02-01
影响因子：
3.9
通讯作者：
Hammarlund-Udenaes, M
中科院分区：
文献类型：
--
作者：
Gupta, A;Chatelain, P;Hammarlund-Udenaes, M
本研究的目的是比较左旋（R-CZE）和西替利嗪（S-CZE）的血脑屏障（BBB）转运和脑分布。将经药物后透析校准的微透析探针置于8只豚鼠的额叶皮质和右颈静脉。外消旋CZE（2.7 mg/kg）以60分钟静脉输注给药。用液相色谱-串联质谱法测定血液和脑中对映体的未结合浓度和总浓度。使用参数K-p、K-p、K-u、K-p、K-uu和V-u、V-br比较CZE对映体的脑分布。K-p将总脑浓度与总血浆浓度进行比较，K-p、K-u补偿血浆中的结合，而K-p、K-uu还补偿脑组织内的结合，并直接定量跨BBB的转运。V-u，V-br描述了大脑内的结合。S-和R-CZE的K-p分别为0.22和0.04，表明立体选择性脑分布是由与血浆蛋白的不同结合引起的。CZE对映体穿过BBB的转运不是立体选择性的，因为K-p、K-uu分别为0.17和0.14（N.S.）分别为S-和R-CZE。K-p、K-uu值显示对映异构体在很大程度上穿过BBB流出。两种对映异构体的Vu，br也相似，约为2.5 ml/g脑，该值表明与脑组织的结合率较高。因此，当确定脑分布的立体选择性时，重要的是研究控制这种分布的所有因素，血液和脑中的结合以及BBB平衡。
The objective of this study was to compare the blood-brain barrier (BBB) transport and brain distribution of levo-(R-CZE) and dextrocetirizine (S-CZE). Microdialysis probes, calibrated using retrodialysis by drug, were placed into the frontal cortex and right jugular vein of eight guinea pigs. Racemic CZE (2.7 mg/kg) was administered as a 60-min i.v. infusion. Unbound and total concentrations of the enantiomers were measured in blood and brain with liquid chromatography-tandem mass spectrometry. The brain distribution of the CZE enantiomers were compared using the parameters K-p, K-p,K-u, K-p,K-uu, and V-u,V-br. K-p compares total brain concentration to total plasma concentration, K-p,K-u compensates for binding in plasma, whereas K-p,K-uu also compensates for binding within the brain tissue and directly quantifies the transport across the BBB. V-u,V-br describes binding within the brain. The stereoselective brain distribution indicated by the K-p of 0.22 and 0.04 for S- and R-CZE, respectively, was caused by different binding to plasma proteins. The transport of the CZE enantiomers across the BBB was not stereoselective, since the K-p,K-uu was 0.17 and 0.14 (N.S.) for S- and R-CZE, respectively. The K-p,K-uu values show that the enantiomers are effluxed to a large extent across the BBB. The Vu, br of approximately 2.5 ml/g brain was also similar for both the enantiomers, and the value indicates high binding to brain tissue. Thus, when determining stereoselectivity in brain distribution, it is important to study all factors governing this distribution, binding in blood and brain, and the BBB equilibrium.