Objective To explore the relationship between concentration of carbamazepine (CBZ) in the extracellular fluid (ECF) of normal brain tissue and the focus region around scar tissue and in plasma in rats. To study whether the extracellular brain concentration of CBZ can be regulated by P-glycoprotein (PGP).Methods Adult male Sprague-Dawley rats were divided into four groups. Group of scar model was established by cold stab injury in cerebral cortex in rats, which was verified histologically one month after. We injected normal group with CBZ (40mg/kg, i.p) and used in vivo microdialysis to collect extracellular fluid of the cerebral cortex from 30min to 120min after CBZ administration. Blood samples were collected 60min after CBZ administration. For inhibition of PGP, group of Verapamil received local application of verapamil via microdialysis probe. After the formation of scar in cerebral cortex in rats, group of scar received the same treatments as normal group. CBZ concentrations in dialysate and plasma samples were determined by chemiluminescence immunoassay method.Results The morphological observation revealed the formation ofscar in cerebral cortex in rats and confirmed that scar model was successfully established. For normal group, the average CBZ concentration in ECF of the cerebral cortex was 0.64+0.26|ig/ml, in plasm was 8.66+4.73ug/ml, the ratio between CBZ in brain dialysate and plasma averaged 0.086+0.03. For group of verapamil, CBZ concentration in ECF was 0.98+0.27ug/ml, in plasma was 9.32+3.35ug/ml, the ratio was 0.112+0.029. For group of scar, CBZ concentration in ECF of the focus region around scar tissue was 0.63+0.28ug/ml , in plasma was 9.95+3.67ug/ml, the ratio was 0.063+0.014. CBZ concentration in plasma was not significantly different among all groups. Local application of the PGP inhibitor verapamil via microdialysis probe in the cortex significantly increased the ECF levels of CBZ, resulting in a significant difference vs group control (P<0.05), and ratio also showed a significant increase (P<0.05). CBZ concentration in ECF of the focus region around scar tissue was lower than that in normal brain tissue but group difference was not significant (P>0.05). Correlation analysis of normal group and group of scar yielded statistically significant correlations between CBZ concentration in ECF and in plasma (Pearson correlation coefficient 0.83, 0.88 respectively).Conclusions CBZ concentration in ECF of the cerebral cortex in rats correlates positively to plasma CBZ concentration. CBZ concentrationin ECF of the focus region around scar tissue is close to that in ECF of normal brain tissue in rats. CBZ is a substrate of PGP and the extracellular brain concentration of CBZ can be regulated by P-glycoprotein (PGP).
|