Prediction of Drug Exposure in the Brain from the Chemical Structure
The level of drug exposure in the brain is long known to relate to the physico-chemical properties of the drug. The study of this relationship has attracted much attention through the years as it holds a promise that this drug property can be predicted in
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Prediction of Drug Exposure in the Brain from the Chemical Structure Markus Fridén
Abstract The level of drug exposure in the brain is long known to relate to the physico-chemical properties of the drug. The study of this relationship has attracted much attention through the years as it holds a promise that this drug property can be predicted in silico from the chemical drug structure. Various in vivo methodologies have been used to define and quantify drug exposure in the brain, the most commonly used parameter being logBB, which is the brain-to-blood ratio of total drug concentrations. From datasets of logBB it has been inferred that drug exposure in the brain is promoted by the lipophilicity, i.e. lipid solubility, of the drug and restricted by its hydrogen bonding potential. Recent work with the Kp,uu,brain parameter, representing a pharmacologically relevant brain-to-blood ratio of unbound drug concentrations, has confirmed the limiting effect of hydrogen bonding on drug exposure in the brain, but also indicated no dependence on lipophilicity. The challenges associated with obtaining high predictivity models for Kp,uu,brain confirm the contemporary view of the blood–brain barrier (BBB) as not only being physical and passive in nature but also involving specific carrier-mediated processes. It follows that in silico approaches need to compliment and merge with experimental methodologies to advance the field of brain exposure predictions.
M. Fridén, Ph.D. (*) Department of Drug Metabolism and Pharmacokinetics, AstraZeneca Research and Development, Respiratory, Inflammation and Autoimmunity Innovative Medicines, Pepparedsleden 1, Mölndal 43183, Sweden e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_11, © American Association of Pharmaceutical Scientists 2014
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M. Fridén
11.1 Introduction For decades it has been recognized that a drug’s ability to cross the blood–brain barrier (BBB) is related to its physicochemical properties. This idea is not only supported by experimental data in animals but also by clinical notions of for example the hydrophilic beta-blocker atenolol having less CNS related side effects than do the more lipophilic propranolol (McAinsh and Cruickshank 1990) (see Fig 11.1 for molecular structures). The relationship with lipophilicity seems to have become common knowledge even amongst clinicians and it has nourished an idea that BBB transport is essentially predictable. This chapter critically reviews the various approaches that have been taken during the years to predict the level of drug exposure in the brain form the chemical structure of the drug. While the computational
Fig. 11.1 Three-dimensional structures of propranolol (top) and atenolol (bottom) coloured according to the electrostatic potential where red and blue areas indicate the negative and positive charges of oxygen and nitrogen atoms (MacroModel v. 8.0, MM3* force field). Not
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