Effects Of Borneol On The Pharmacokinetics And Brain Tissue Distribution Of Carbamazepine

Objective:The main purpose of this study was to illustrate the effects of borneol on the pharmacokinetics and brain tissue distribution of carbamazepine. The other purpose was to explore the effects of different gastrointestinal release site on its pharmacokinetics. Finally, the solid dispersion of carbamazepine-borneol was prepared and evaluated in vitro.Methods:1. The rats were administrated ethanol solution (50%), borneol (200 mg·kg-1) and verapamil (25 mg·kg-1) for inducing 7 days, respectively, and intragastric carbamazepine (CBZ) (120 mg-kg"') after 20 min at last administration. The concentrations of CBZ in the plasma and brain tissue of rats were determined by HPLC. The mobile phase was methanol-water (0.1% phosphoric acid) (48:52, v/v) at a flow rate of 1.0 mL·min-1, and 20μl of injection volume was eluted in a reverse phase column (Kromasil C18,5μm,4.6×150 mm). The pharmacokinetic parameters were computed by software program DAS 2.0.2. The effects of different gastrointestinal release site on CBZ pharmacokinetics:The rats were given carbamazepine tablet and enteric capsules (70 mg/rat). And the concentrations of CBZ in the plasma were determined by HPLC. The pharmacokinetic parameters were computed by software program DAS 2.0.3. The preparation of CBZ-Borneol (3:5, w/w) solid dispersion:The solid dispersion of was prepared by melting methods with polymer at different CBZ-Borneol:PEG 4000 ratios (1:1,1:2, 1:5, and 1:10). Furthermore, the solubility and dissolution of this solid dispersion were illustrated in vitro.Results:1. The effects of borneol on the pharmacokinetics of carbamazepine:There was obvious difference on the pharmacokinetic parameters of the borneol group and control group, such as:AUC(0-8) (mg·L-1h) (12.12±1.62 vs 5.42±0.55), Cmax(mg·L-1)(4.07±0.19 vs 2.24±0.21), (P<0.05). The pharmacokinetic parameters of the verapamil group is:AUC (0-8) 15.96±2.17 mg·L-1·h, Cmax3.88±0.16 mg-L"'. Similarity with verapamil, the pharmacokinetics parameters of carbamazepine could be affected by borneol. But the effects of borneol were weaker than that of verapamil. 2. The effects of borneol on the brain tissue distribution of carbamazepine:The results of brain distribution showed that the brain concentration of CBZ could be increased by borneol. The CBZ brain concentrations of the borneol group and control group have obvious difference at different time, such as:15 min (1.88±0.04 vs 1.48±0.14g·mL-1),60 min (1.62±0.05 vs 1.46±0.38μg·mL-1),120 min (0.84±0.04 vs 0.42±0.05μg·mL-1), (P<0.05).3. The effects of different gastrointestinal release site on CBZ pharmacokinetics:There was obvious difference on the pharmacokinetic parameters after intragastric carbamazepine tablet and enteric capsules. The pharmacokinetic parameters were AUC(0-14) (mg·L-1h) (25.07±8.95 vs 35.83±7.93),AUC(0-∞) (mg·L-1·h) (34.95±9.24 vs 49.64±7.80). Therefore, the bioavailability of CBZ could be improved when CBZ was released at intestinal tract.4. The preparation of CBZ-Borneol (3:5, w/w) solid dispersion:The higher solubilities of CBZ were observed when polyethylene glycol (PEG) 4000 was used as carriers in the solid dispersion. The solubilities were 0.16 mg·mL-1 (1:1),0.19 mg·mL-1 (1:2),0.28 mg·mL-1(1:5),0.33 mg·mL-1 (1:10). And more than 90% drug was released from this CBZ-Borneol solid dispersion within 20 min, but only 80% from the ordinary tablet. And the dissolution rate of carbamazepine from solid dispersion was markedly enhanced by increasing the PEG 4000 concentration.Conclusions:The borneol has the improving effect on the bioavailability and brain tissue distribution of CBZ. The mechanisms of borneol on the enhancing effect on absorption and distribution of CBZ might be inhibiting the exocytosis of P-gp and improving the permeability of the blood-brain barrier (BBB). And this paper inllustrated the enteric formulations can increase the solubilities and absorption of CBZ at intestine. And the results suggested that solid dispersion is a powerful tool to accelerate dissolution rates and solubilities.