Brain Distribution of Drugs: Pharmacokinetic Considerations
It is crucial to understand the basic principles of drug transport, from the site of delivery to the site of action within the CNS, in order to evaluate the possible utility of a new drug candidate for CNS action, or possible CNS side effects of non-CNS t
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Contents 1 Introduction to CNS Drug Distribution 2 Key Parameters for Characterization of CNS Drug Distribution 2.1 Drug Transport Across CNS Barriers with Focus on BBB and BCSFB 2.2 Drug Distribution within the Brain Parenchyma 3 Small vs Large Molecules: Pharmacokinetic Differences 4 Optimization of Experimental Design for Neuropharmacokinetic Studies 5 Conclusions and Future Directions References
Abstract
It is crucial to understand the basic principles of drug transport, from the site of delivery to the site of action within the CNS, in order to evaluate the possible utility of a new drug candidate for CNS action, or possible CNS side effects of non-CNS targeting drugs. This includes pharmacokinetic aspects of drug concentration-time profiles in plasma and brain, blood–brain barrier transport and drug distribution within the brain parenchyma as well as elimination processes from the brain. Knowledge of anatomical and physiological aspects connected with drug delivery is crucial in this context. The chapter is intended for professionals working in the field of CNS drug development and summarizes
I. Loryan (*) · M. Hammarlund-Udenaes Translational PKPD Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden e-mail: [email protected]; [email protected]; [email protected] S. Syvänen Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden e-mail: [email protected] # Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_405
I. Loryan et al.
key pharmacokinetic principles and state-of-the-art experimental methodologies to assess brain drug disposition. Key parameters, describing the extent of unbound (free) drug across brain barriers, in particular blood–brain and blood– cerebrospinal fluid barriers, are presented along with their application in drug development. Special emphasis is given to brain intracellular pharmacokinetics and its role in evaluating target engagement. Fundamental neuropharmacokinetic differences between small molecular drugs and biologicals are discussed and critical knowledge gaps are outlined. Keywords
Biologicals · Brain barriers · Brain slice uptake · Free drug hypothesis · Intracellular pharmacokinetics · Kp,uu,brain · Neuropharmacokinetics · Small molecules
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Introduction to CNS Drug Distribution
Most drugs are delivered to the brain via blood after enteral or parenteral administration. This means that the blood–brain barrier (BBB), the wall of brain capillaries, is the interface through which a drug reaches the brain. Thus, BBB interactions with drug molecules by passive transport, active efflux or active uptake, determine how much of the drug is delivered to the brain. The presence of the BBB throughout the brain creates a contact surface for drug delivery to the whole brain parenchyma, as the BBB is characterized by a large surface area and short distances between capillaries. The disadvantage or advantage, d
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