Why look for the key where you lost it when you can look for it where there is more light?

Treatment of diseases of the brain is an important and costly part of health care. Despite this, several big pharma have significantly reduced or quit research in this area. Here are some views on preclinical science aspects of the problem and how to address it.

There are so many misunderstandings of the blood-brain barrier (BBB) and its role in drug delivery to the brain. The statement that “98 % of all drugs do not pass the BBB” is repeated frequently, but has actually not been proven scientifically 1. What is “do not pass”? What does 98 % refer to? Rate or extent? How is it measured? Is it the active drug or the combination of active and nonspecifically bound (total) brain concentrations?

Hopefully we can go away from the simplistic view, where life (read drug discovery and development) is either black or white (or rather red or green), to include the shades that may be as important. But then we need to use more of our intellect and less of our automated systems in decision making.

“Small molecular drugs generally do pass the BBB, but for some of them not in high enough quantities to exert their action within the CNS”

Small molecular drugs generally do pass the BBB, but for some of them not in high enough quantities to exert their action within the CNS. And yes, there are several active efflux transporters that hinder uptake into the brain. And yes, the efflux systems seem to be the most prominent ones influencing drug concentrations in the brain (although there are also influx transporters for drugs that improve their uptake, like for oxycodone and diphenhydramine) 2-4.

And yes, some of the drugs have a really low extent of transport to the brain, precluding them from action within the brain, luckily for antihistamines which results in less sedation, and less lucky for other drugs. But some drugs with a rather low extent of transport to the brain are anyway active (paliperidone), and some drugs that are very slowly entering the brain are also active (morphine) 5. Fortunately, these were developed before the strict red-green high-throughput rules were adopted in drug discovery.

The first thing that is needed and that is in progress presently is to go away from measuring total concentrations to measure the unbound, pharmacologically active concentrations in the brain 6. We have shown that the difference between drugs in how much is total vs unbound in the brain can be 1:1 to 3000:1 7. Measuring everything that is present in the brain could therefore be 3000-fold wrong or quite correct, but we do not know that up-front. It has nothing to do with which type of drug it is (but it is somewhat related to lipophilicity). The 3000-fold error-drug looks like a perfect candidate as there is “so much in the brain” if the wrong measures are made, and they have been.

The other misunderstanding is thinking that principles of BBB transport work the same way as for the intestinal barrier. Here there are profound differences in vivo. We have shown that the most important measurement is the extent of transport and not the rate of transport across the BBB (permeability) 5. This is even more difficult to change as a concept than the use of unbound concentrations as the most suitable measure. The conclusion made from our studies is that if a drug has a high enough permeability for oral absorption, there is no problem whatsoever regarding high enough permeability for BBB transport.

So why have several big (and smaller) pharma given up on CNS drug development?

Too difficult? Too expensive? Too slow? The historical misunderstandings on what measures (not) to use, as mentioned above, is an important part. But we cannot either dismiss the huge problems with finding good preclinical models for CNS diseases. However, let us continue on the concentration-pathway and see what can actually be done.

Today there are, partly through our contributions, developed methods and concepts for how to think about clinically relevant drug delivery to the brain.

“The other misunderstanding is thinking that principles of BBB transport work the same way as for the intestinal barrier.”

It is possible to estimate unbound brain concentrations through rather simple methods. A combination of total brain and total plasma concentration measurements in vivo, brain slice and brain homogenate measurements in vitro, and plasma protein binding in vitro gives important information about the BBB transport in early discovery 7. The ratio of unbound brain to unbound blood (Kp,uu), gives strong indications together with potency measurements on how successful a drug candidate is. And combining brain slice and brain homogenate measurements gives even further information on intracellular distribution and side-effect indications like lysosomotropism 8. Positive aspects are possibilities to measure if potential intracellular drug target in acidic subcellular structures receive enough drug.

It is our responsibility not to give up, but to use scientific thinking to progress the CNS drug area. CNS diseases are today a huge burden on society, and will be even more so in the future 9. It has been shown that in relation to societal costs, CNS diseases are under-represented regarding funding both in drug industry and from societal funding bodies, compared to other serious disease areas 10.

A contribution to improved understanding of this area has been made recently 11, that hopefully will contribute with a widened understanding and knowledge about the BBB and different approaches that can be made to solve the vast problems of treating CNS diseases.


1. W.M. Pardridge. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2:3-14 (2005).

2. M. Friden, S. Winiwarter, G. Jerndal, O. Bengtsson, H. Wan, U. Bredberg, M. Hammarlund-Udenaes, and M. Antonsson. Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J Med Chem. 52:6233-6243 (2009).

3. E. Bostrom, U.S. Simonsson, and M. Hammarlund-Udenaes. In vivo blood-brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug metabolism and disposition: the biological fate of chemicals. 34:1624-1631 (2006).

4. M.W. Sadiq, A. Borgs, T. Okura, K. Shimomura, S. Kato, Y. Deguchi, B. Jansson, S. Bjorkman, T. Terasaki, and M. Hammarlund-Udenaes. Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. Journal of pharmaceutical sciences. 100:3912-3923 (2011).

5. M. Hammarlund-Udenaes, M. Friden, S. Syvanen, and A. Gupta. On the rate and extent of drug delivery to the brain. Pharmaceutical research. 25:1737-1750 (2008).

6. M. Hammarlund-Udenaes. Active-site concentrations of chemicals – are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol. 106:215-220 (2010).

7. M. Friden, F. Ducrozet, B. Middleton, M. Antonsson, U. Bredberg, and M. Hammarlund-Udenaes. Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug metabolism and disposition: the biological fate of chemicals. 37:1226-1233 (2009).

8. I. Loryan, M. Friden, and M. Hammarlund-Udenaes. The brain slice method for studying drug distribution in the CNS. Fluids and barriers of the CNS. 10:6 (2013).

9. J. Olesenand M. Leonardi. The burden of brain diseases in Europe. European journal of neurology : the official journal of the European Federation of Neurological Societies. 10:471-477 (2003).

10. M.E. Schwaband A.D. Buchli. Drug research: plug the real brain drain. Nature. 483:267-268 (2012).

11. Drug Delivery to the Brain – Physiology, Methodologies and Approaches”, Eds Hammarlund-Udenaes, de Lange and Thorne (Springer 2014).



About the author:

Dr Hammarlund-Udenaes has been Professor of Pharmacokinetics and Pharmacodynamics at Uppsala University, Sweden, since 1999. She is heading the Translational PKPD Group at the Department of Pharmaceutical Biosciences. She has supervised 15 PhD’s and published close to 100 original articles. She became an AAPS Fellow in 2005, and is one of the Editors of the journal Pharmaceutical Research, and on the Editorial Advisory Board of Journal of Pharmaceutical Sciences and Fluids and Barriers of the CNS. Dr Hammarlund-Udenaes is the Chair of the Gordon Conference on Barriers of the CNS in 2014. She has spent sabbaticals at the University of California San Francisco and at Tohoku University, Sendai, Japan.

The research is focused on blood-brain barrier transport of drugs in relation to central effects with a translational perspective to humans. Drug delivery to the brain is theoretically as well as experimentally studied with microdialysis, PET, and the brain slice method. New concepts for understanding brain drug delivery are developed. The role of nano-delivery for small and larger molecules is also investigated.

Dr Hammarlund-Udenaes is consulting with drug industry regarding discovery methods and interpretations of data of drug delivery to the brain to optimize selection of compounds both for CNS and non-CNS action. She holds the annual course “The blood-brain barrier in CNS Drug Development” together with Dr ECM de Lange, Leiden University. She has recently edited the book “Drug Delivery to the Brain – Physiological Concepts, Methodologies and Approaches”, that is coming out early 2014, together with Dr’s ECM de Lange and Robert Thorne.

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Closing thought: Why have several big (and smaller) pharma companies given up on CNS drug development??