BRAIN, LIVER AND BLOOD DISTRIBUTION KINETICS OF CARBAMAZEPINE AND ITSMETABOLIC INTERACTION WITH CLOMIPRAMINE IN RATS - A QUANTITATIVE MICRODIALYSIS STUDY

The aim of this work was to study the transport across the blood-brain barrier (BBB), blood and liver distribution kinetics, metabolic inter action and local liver metabolism of carbamazepine (CBZ) in the rat, u sing microdialysis with the internal standard technique as in vivo cal ibration method. CBZ and its major metabolite, carbamazepine-10,11-epo xide (CBZ-EPO), are homogeneously distributed to hippocampus and cereb ellum. The ratios of the areas under the concentration-time curve (AUC ) for both brain regions to blood AUC were not different from unity fo r CBZ; they were 0.46 +/- 0.08 (hippocampus) and 0.45 +/- 0.05 (cerebe llum) for CBZ-EPO, In addition, the disposition of CBZ and CBZ-EPO in blood and liver, after a single dose of CBZ, was studied in control an imals and in rats after pretreatment with clomipramine (CLOMI). A 2-fo ld increase in the blood AUC of CBZ and a decrease to 33% of the blood AUC of CBZ-EPO in the pretreated group demonstrate the metabolic inhi bition of CBZ-EPO formation by clomipramine. The ratios of the AUG(CBZ -EPO) to the AUG(CBZ), as a measure of CBZ-EPO formation, were not dif ferent for blood and liver within the control and the clomipramine-pre treated groups, but the ratios were significantly lower for liver and blood in the clomipramine group compared with the control animals. In addition, CBZ was administered locally in the extracellular fluid of t he liver via the microdialysis probe. The liver metabolic ratio, expre ssed as the ratio of the formed CBZ-EPO concentration to the CBZ conce ntration administered, ranged from 18.2 +/- 1.2% to 19.6 +/- 1.6%.