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

Abstract

Please cite this article as: Fortuna, A., Alves, G., Soares-da-Silva, P., Falcão, A., Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: new set of data for predictive in silico ADME models, Epilepsy Research (2013), http://dx.doi.org/10.1016/j.eplepsyres. 2013.08.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractIn silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programs. 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 (1.4 mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12 h 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 AUC 0-12h 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 ...

Lipid-Core Nanocapsules Act as a Drug Shuttle Through the Blood Brain Barrier and Reduce Glioblastoma After Intravenous or Oral Administration

“…17 The formulation exhibited a pink homogeneous turbid aspect with no aggregate or precipitate. Laser diffraction analysis revealed an unimodal distribution with D [4,3] of 320 ± 84 nm and SPAN of 1 55 ± 0 22 (Fig. 2).…”

“…2). A control LNC formulation without any labeling was also prepared with D [4,3] and SPAN values of 254 ± 61 nm and 1 54 ± 0 16, respectively (Fig. 2).…”

“…D [4,3] is calculated using Eq. (1), and SPAN is calculated by dividing the difference of the cumulative diameters of 90% and 10% of the distribution curve (volume) by the median diameter (volume).…”

“…The formulations were analyzed by laser diffraction (Mastersizer ® 2000, Malvern, UK) to determine their particle size distribution, volume-weighted mean diameter (D [4,3]) and polydispersity (SPAN). D [4,3] is calculated using Eq.…”

“…1 The BBB drug. 4 Therefore, facilitation in drug penetrability through the BBB may greatly improve treatments by allowing the accumulation of drugs in the CNS. Additionally, lower doses could be employed, reducing adverse systemic effects.…”