Binding of licarbazepine enantiomers to mouse and human plasma proteins

Fortuna, Ana; Alves, Gilberto; Soares-da-Silva, Patrı́cio

doi:10.1002/bdd.716

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…Further studies also showed that stereoselective differences are dependent on species 28,29 . Nevertheless, mammalian results are occasionally consistent with human disposition 64 . For example, the in vitro concentration ratios of R -MK0767 to S -enantiomer were similar in dog and human plasma (1.5–1.7), but the stereoselectivities in rat and rabbit plasma were inverted 65 .…”

Section: Stereoselectivity Of Plasma Protein Binding To Chiral Drugsmentioning

confidence: 90%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.

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Section: Stereoselectivity Of Plasma Protein Binding To Chiral Drugsmentioning

confidence: 90%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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“…Flesch et al reported that approximately 40% of MHD was bound to serum proteins, predominantly ALB. However, Fortuna et al demonstrated that the disposition of MHD was not dependent on its affinity to plasma proteins. Due to the sample size and type of data points in our study, the influence of the above factors on MHD exposure requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

et al. 2019

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Summary What is known and objectives Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10‐hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. Methods Ninety‐one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients’ clinical data were recorded. PPK analysis was performed using a non‐linear, mixed‐effect modelling approach. The goodness‐of‐fit (GOF) plots, bootstrap method, prediction‐corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady‐state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. Results A one‐compartment model with first‐order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h−1, respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20‐30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. What is new and conclusion A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.

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“…The concentration used for measuring the PPB of each test compound was defined according to previous studies and included the therapeutic range of compounds (Fortuna et al, 2010(Fortuna et al, , 2012b.…”

Section: Plasma Protein Binding Of Cbz and Its Derivativesmentioning

confidence: 99%

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

et al. 2013

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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 ...

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Binding of licarbazepine enantiomers to mouse and human plasma proteins

Cited by 11 publications

References 36 publications

Stereoselective binding of chiral drugs to plasma proteins

Stereoselective binding of chiral drugs to plasma proteins

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy

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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