Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery

ABSTRACTPurposeThe current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.MethodsForty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (Kp,uu,brain) and cell (Kp,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.ResultsAssessment of Kp,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. Kp,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.ConclusionsWith the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.

[1]  M. Hammarlund-Udenaes.  Active-site concentrations of chemicals - are they a better predictor of effect than plasma/organ/tissue concentrations? , 2010, Basic & clinical pharmacology & toxicology.

[2]  E. D. De Lange.  Utility of CSF in translational neuroscience , 2013, Journal of Pharmacokinetics and Pharmacodynamics.

[3]  E. Jonsson,et al.  BRAIN DISTRIBUTION OF CETIRIZINE ENANTIOMERS: COMPARISON OF THREE DIFFERENT TISSUE-TO-PLASMA PARTITION COEFFICIENTS: Kp, Kp,u, AND Kp,uu , 2006, Drug Metabolism and Disposition.

[4]  Bill J Smith,et al.  Progress in Brain Penetration Evaluation in Drug Discovery and Development , 2008, Journal of Pharmacology and Experimental Therapeutics.

[5]  Yuichi Sugiyama,et al.  Impact of Drug Transporter Studies on Drug Discovery and Development , 2003, Pharmacological Reviews.

[6]  D. Swinney,et al.  How were new medicines discovered? , 2011, Nature Reviews Drug Discovery.

[7]  Stina Syvänen,et al.  On The Rate and Extent of Drug Delivery to the Brain , 2007, Pharmaceutical Research.

[8]  Anders Tunek,et al.  High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery. , 2007, Journal of medicinal chemistry.

[9]  Ulf Bredberg,et al.  Measurement of Unbound Drug Exposure in Brain: Modeling of pH Partitioning Explains Diverging Results between the Brain Slice and Brain Homogenate Methods , 2011, Drug Metabolism and Disposition.

[10]  L. Di,et al.  Demystifying brain penetration in central nervous system drug discovery. Miniperspective. , 2013, Journal of medicinal chemistry.

[11]  Elliot A. Ludvig,et al.  Comparative psychology and the grand challenge of drug discovery in psychiatry and neurodegeneration , 2012, Behavioural Processes.

[12]  S. Apparsundaram,et al.  Unbound Brain Concentration Determines Receptor Occupancy: A Correlation of Drug Concentration and Brain Serotonin and Dopamine Reuptake Transporter Occupancy for Eighteen Compounds in Rats , 2009, Drug Metabolism and Disposition.

[13]  K. Read,et al.  Receptor Occupancy and Brain Free Fraction , 2009, Drug Metabolism and Disposition.

[14]  R. Wennberg,et al.  Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by Bilirubin at the Blood-CSF and Blood-Brain Barriers in the Gunn Rat , 2011, PloS one.

[15]  J. Krise,et al.  Cationic amphiphilic drugs cause a marked expansion of apparent lysosomal volume: implications for an intracellular distribution-based drug interaction. , 2012, Molecular pharmaceutics.

[16]  Danny D Shen,et al.  Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. , 2004, Advanced drug delivery reviews.

[17]  Muralikrishna Duvvuri,et al.  A novel assay reveals that weakly basic model compounds concentrate in lysosomes to an extent greater than pH-partitioning theory would predict. , 2005, Molecular pharmaceutics.

[18]  C. L. Shaffer.  Defining Neuropharmacokinetic Parameters in CNS Drug Discovery to Determine Cross-Species Pharmacologic Exposure–Response Relationships , 2010 .

[19]  Jeffrey P Krise,et al.  Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. , 2007, Journal of pharmaceutical sciences.

[20]  R. Bendayan,et al.  Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System , 2006, Pharmacological Reviews.

[21]  Jiunn H. Lin,et al.  CSF as a surrogate for assessing CNS exposure: an industrial perspective. , 2008, Current drug metabolism.

[22]  P. Jeffrey,et al.  Challenges for blood–brain barrier (BBB) screening , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[23]  Arup K. Ghose,et al.  Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery , 2011, ACS chemical neuroscience.

[24]  A. Reichel.  Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept , 2009, Chemistry & biodiversity.

[25]  Simone Braggio,et al.  Assessing brain free fraction in early drug discovery , 2010, Expert opinion on drug metabolism & toxicology.

[26]  T. Maurer,et al.  Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery , 2002, Biopharmaceutics & drug disposition.

[27]  Geri A. Sawada,et al.  Early Preclinical Evaluation of Brain Exposure in Support of Hit Identification and Lead Optimization , 2006 .

[28]  B. Fichtl,et al.  Binding of drugs to tissues. , 1983, Drug metabolism reviews.

[29]  C. Nicholson,et al.  Extracellular space structure revealed by diffusion analysis , 1998, Trends in Neurosciences.

[30]  Paul Morgan,et al.  Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. , 2012, Drug discovery today.

[31]  Ulf Bredberg,et al.  Development of a High-Throughput Brain Slice Method for Studying Drug Distribution in the Central Nervous System , 2009, Drug Metabolism and Disposition.

[32]  M. Monshouwer,et al.  Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid , 2009, Drug Metabolism and Disposition.

[33]  C. Bundgaard,et al.  Associating in vitro target binding and in vivo CNS occupancy of serotonin reuptake inhibitors in rats: The role of free drug concentrations , 2012, Xenobiotica; the fate of foreign compounds in biological systems.

[34]  J. DiMasi,et al.  Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs , 2010, Clinical pharmacology and therapeutics.

[35]  Russell Mortishire-Smith,et al.  Development and Validation of a Higher-Throughput Equilibrium Dialysis Assay for Plasma Protein Binding , 2011, Journal of laboratory automation.

[36]  J. Krise,et al.  Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications , 2012, Expert opinion on drug metabolism & toxicology.

[37]  J. DiMasi,et al.  Pharmaceutical Innovation in the 21st Century: New Drug Approvals in the First Decade, 2000–2009 , 2011, Clinical pharmacology and therapeutics.

[38]  R. Bendayan,et al.  Cellular localization and functional expression of P‐glycoprotein in rat astrocyte cultures , 2004, Journal of neurochemistry.

[39]  M. Hammarlund-Udenaes,et al.  The brain slice method for studying drug distribution in the CNS , 2013, Fluids and Barriers of the CNS.

[40]  Susanne Winiwarter,et al.  Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. , 2009, Journal of medicinal chemistry.

[41]  U. Bredberg,et al.  Methodologies to assess brain drug delivery in lead optimization. , 2009, Current topics in medicinal chemistry.

[42]  James E Audia,et al.  Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor , 2011, The Journal of Neuroscience.

[43]  Ulf Bredberg,et al.  Improved Measurement of Drug Exposure in the Brain Using Drug-Specific Correction for Residual Blood , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[44]  R. Bendayan,et al.  Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. , 2001, Pharmacological reviews.

[45]  H. Pajouhesh,et al.  Medicinal chemical properties of successful central nervous system drugs , 2005, NeuroRX.

[46]  Andreas Reichel,et al.  The role of blood-brain barrier studies in the pharmaceutical industry. , 2006, Current drug metabolism.

[47]  R. Schreiber,et al.  Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance , 2004, Neuropharmacology.

[48]  U. Bredberg,et al.  In Vitro Methods for Estimating Unbound Drug Concentrations in the Brain Interstitial and Intracellular Fluids , 2007, Drug Metabolism and Disposition.

[49]  R. Bendayan,et al.  In Situ Localization of P-glycoprotein (ABCB1) in Human and Rat Brain , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[50]  D. Selley,et al.  Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC50,u and Correlation of in Vitro, Preclinical, and Clinical Data , 2007, Journal of Pharmacology and Experimental Therapeutics.

[51]  B. McEwen,et al.  Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. , 2001, Annual review of pharmacology and toxicology.