Article

Toward the prediction of CNS drug-effect profiles in physiological and pathological conditions using microdialysis and mechanism-based pharmacokinetic-pharmacodynamic modeling.

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, 2300 RA, Leiden University, Leiden, The Netherlands.
The AAPS Journal (Impact Factor: 3.91). 02/2005; 7(3):E532-43. DOI: 10.1208/aapsj070354
Source: PubMed

ABSTRACT Our ultimate goal is to develop mechanism-based pharmacokinetic (PK)-pharmacodynamic (PD) models to characterize and to predict CNS drug responses in both physiologic and pathologic conditions. To this end, it is essential to have information on the biophase pharmacokinetics, because these may significantly differ from plasma pharmacokinetics. It is anticipated that biophase kinetics of CNS drugs are strongly influenced by transport across the blood-brain barrier (BBB). The special role of microdialysis in PK/PD modeling of CNS drugs lies in the fact that it enables the determination of free-drug concentrations as a function of time in plasma and in extracellular fluid of the brain, thereby providing important data to determine BBB transport characteristics of drugs. Also, the concentrations of (potential) extracellular biomarkers of drug effects or disease can be monitored with this technique. Here we describe our studies including microdialysis on the following: (1) the evaluation of the free drug hypothesis; (2) the role of BBB transport on the central effects of opioids; (3) changes in BBB transport and biophase equilibration of anti-epileptic drugs; and (4) the relation among neurodegeneration, BBB transport, and drug effects in Parkinson's disease progression.

Download full-text

Full-text

Available from: Elizabeth De Lange, Jun 28, 2015
0 Followers
 · 
104 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Epilepsy research 09/2013; 107(1-2). DOI:10.1016/j.eplepsyres.2013.08.013 · 2.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The need to discover and develop safe and effective new medicines is greatest for disorders of the CNS. A core requirement for an effective neurotherapeutic agent is an ability to cross the blood–brain barrier and remain in the brain interstitial fluid (ISF) for a sufficient duration and concentration to evoke the desired therapeutic effect. Measuring the free concentration of a neuroactive compound in brain ISF is therefore an essential step in the critical path towards the development of a CNS medicine. In vivo microdialysis provides a powerful method for the measurement of endogenous and exogenous substances in the ISF surrounding the probe and so it represents an important tool in CNS drug discovery. It can also be used to measure the pharmacodynamic response of neuroactive compounds by measuring neurotransmitters and second messengers. Another approach to measure both pharmacokinetics and the pharmacodynamics of neuroactive compounds is the measurement of receptor occupancy, which has the advantage of being applicable to the study of humans as well as experimental animals. Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds clearly improve understanding of the efficacy and safety of drug candidates, which improves both the efficiency and the effectiveness of CNS medicines research.
    Neurobiology of Disease 01/2010; 37(1-37):38-47. DOI:10.1016/j.nbd.2009.09.025 · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The added value of using microdialysis in PK/PD research is that it gives an opportunity for direct measurement of drug concentrations close to the site of action and PD effects in parallel, thus furthering our understanding of relationships at the local target site. This area has a large potential that is not yet fully utilized. With the use of large pore size probes it may also be possible to measure larger molecules as biomarkers of drug action. Drug PK studies with microdialysis in tissues can also be combined with other types of PD measurements to obtain PK/PD relationships. Areas that benefit from this approach are early drug development, where drug selection based on both PK and PD is crucial, and studies of the influence of disease states on drug distribution and effects. The brain as a target for drug action is in special focus due to the blood-brain barrier hindering drug transport. The main target areas studied so far are PK/PD relationships in brain of opioids and antiepileptics, and antibiotic distribution in muscle and adipose tissue during different conditions.
    Handbook of Behavioral Neuroscience 01/2006; 16:589-600. DOI:10.1016/S1569-7339(06)16031-2