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Plasma and brain pharmacokinetic profiles of carbamazepine and nine derivatives after oral administration to mice: implications for selection of drug candidates Introduction: Epilepsy affects 50 million people worldwide and despite the wide variety of antiepileptic drugs (AEDs) available for seizure control, approximately 30% of epileptic patients do not respond adequately to the pharmacotherapy1. Therefore, research of new anticonvulsant drugs with safer therapeutic indexes and better efficacy is clearly warranted. A strategy successfully applied in the development of new AEDs pipeline consists in designing second and follow-up generations of existing AEDs [such as carbamazepine (CBZ)] in order to maintain the mechanism of action, improving the pharmacokinetic characteristics, safety and/or tolerability profile2. Regarding the pharmacokinetic evaluation during development of oral AEDs, intestinal bioavailability and penetration into the brain (biophase) are required as critical parameters for the proposed anticonvulsant indication. Aim: The objectives of the current study included investigation of the relative plasma and brain exposure after oral administration to mice of CBZ and nine derivatives with distinct in vitro and in vivo pharmacodynamics properties. It was also intended to develop equations for estimation of drug brain concentrations considering those obtained in plasma. Finally, the study also aimed at evaluating the influence of molecular mass (MM), pKa, lipophilicity and polar surface area (PSA) on plasma-brain distribution of test compounds. Methods: In order to achieve those aims, single doses (1.4 mmol/kg) of CBZ, oxcarbazepine (OXC), eslicarbazepine acetate, eslicarbazepine, R-licarbazepine, carbamazepine-10,11-epoxide (CBZ-E), 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine (trans-diol), BIA 2-024, BIA 2-059 and BIA 2-265 were administered to groups of adult male CD-1 mice (n=4) by oral gavage. Blood and brain tissue were taken at 0.25, 0.5, 1, 2, 4, 8 and 12 h post-dosing and plasma and brain drug concentrations were determined by HPLC-UV. The mean concentration-time profiles obtained were analysed by non-compartmental model using WinNonlin® in order to determine peak concentration (Cmax) of compounds in plasma and brain tissue, their time to reach Cmax (tmax) and area under the curve from time zero to the last sampling time (AUC0-12). All experimental procedures were approved by the Portuguese Veterinary General Division. Results: The analysis of the pharmacokinetic profiles of the ten compounds clearly demonstrated that all of them are quickly absorbed from mice gastrointestinal tract, except BIA 2-024 which reaches Cmax only 2 h after its administration. All compounds presented brain/plasma ratios (considering Cmax and AUC0-12h) lower than 1.0, suggesting that BBB restricts drug entry into the brain. CBZ, CBZ-E and OXC exhibited similar tissue-to-plasma ratios at all time points, indicating that distribution equilibrium had been achieved between plasma and brain during the experimental procedure. Furthermore the present investigation clearly found correlations between plasma and brain concentrations for the test set of compounds, supporting linear equations to predict pharmacokinetics in the biophase. Results also showed that MM and PSA were strongly correlated with brain/plasma ratios. Conclusion: A new approach integrating in vivo pharmacokinetic studies and physicochemical characteristics was herein suggested in order to contribute for a rational drug design of new CBZ derivatives. References: 1Luszczki J.J. Pharmacol. Rep. 61 (2009) 197-216. 2Rogawski, M.A. Epilepsy Res. 69 (2006) 273-294. Acknowledgements: BIAL (Portela & Cª, S.A., Portugal) and Fundação para a Ciência e a Tecnologia (SFRH/BD/31390/2006).
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