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Epilepsy Res. 2013 Nov;107(1-2):37-50. doi: 10.1016/j.eplepsyres.2013.08.013. Epub 2013 Sep 3.

Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models.

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Department of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.


In silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programmes. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models. For this purpose, a single dose of each compound (1.4mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure. The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain/plasma ratios (>0.50), followed by eslicarbazepine, R-licarbazepine, trans-diol and BIA 2-024 (ratios within 0.05-0.50). BIA 2-265 was not found in the biophase, probably due to its high plasma-protein bound fraction (>90%) herein revealed for the first time. The comparative in vivo pharmacokinetic data obtained in the present work might be usefully applied in the context of discovery of new antiepileptic drugs that are derivatives of CBZ.


10,11-trans-dihydroxy-10,11-dihydro-carbamazepine; ADME; AEDs; AUC; Antiepileptic drugs; BBB; Brain; C(max); CBZ; CBZ-E; CNS; Carbamazepine; DMSO; ED(50); ESL; HPLC; IS; In silico; LOQ; MES; MRT; NSB; OXC; PPB; Pharmacokinetics; Plasma protein binding; R-Lic; R-licarbazepine; S-Lic; S-licarbazepine; TD(50); UF; absorption distribution metabolism and excretion; antiepileptic drugs; apparent terminal elimination half-life; area under the plasma drug concentration–time curve; blood–brain barrier; carbamazepine; carbamazepine-10,11-epoxide; central nervous system; dimethyl sulfoxide; effective dose for protecting at 50%; eslicarbazepine acetate; high performance liquid chromatography; internal standard; limit of quantification; lowest median toxic dose at 50%; maximal electroshock seizure; maximum peak concentration; mean residence time; non-specific binding; oxcarbazepine; plasma protein binding; t(1/2); t(max); time to reach maximum peak concentration; trans-diol; ultrafiltration

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