The Pharmaceutical Journal
Vol 273 No 7322 p599
23 October 2004

This article
Reprint   Photocopy

PDF 90K, Acrobat Reader

· Concordance
· Medicines distribution
· Pharmacy education
· Management training
· Medicines stability
· New contract
· Technicians
· Prescription charge
· Personal control
· Private dispensing
· Dispensing
· Health services
· Drug delivery
· The Society
· The Journal

Letters to the Editor

Drug delivery

We are well on the way to understanding the blood brain barrier

From Professor J. C. Dearden, Hon MRPharmS

May I add to the comments made by Jenny Bryan in her article “Crossing the blood-brain barrier: drug delivery to the brain is still elusive” (PJ, 2 October, p475) and the letter from Mohammad Alavijeh (PJ, 9 October, p516)? I concur with Dr Alavijeh’s comment that “we are still far from fully understanding the complexity of the brain”. Nevertheless, we have learnt a great deal about the molecular requirements for drugs to be able to cross the BBB effectively, and much of what we know has come from quantitative structure-activity relationship (QSAR) studies. Many years ago Hansch et al¹ showed that one of the key factors controlling the crossing of the BBB by drugs was their hydrophobicity, as represented by the logarithm of the octanol-water partition coefficient (log P), and that a log P value of around 2 was optimal in this respect. This was exemplified by a cardiotonic drug candidate (log P 2.59) which gave rise to “bright colour vision” due to central nervous system penetration; when a small molecular modification lowered the log P value to 1.17, there was negligible loss of efficacy but the “bright colour vision” problem disappeared.

Partition coefficient is a composite property, with components of molecular size, polarity, polarisability and hydrogen bonding. The linear solvation energy descriptors developed by Abraham reflect these components, and Abraham et al² have shown that they can model BBB penetration well: (see PDF 45K)

It can be inferred from equation (1) that the best penetration of the BBB is achieved by large non-polar, non-hydrogen bonding drugs. Others such as van de Waterbeemd and Kansy³ have suggested that small drug molecules penetrate the BBB better; van de Waterbeemd et al⁴ have given the optimal requirements for crossing the BBB as log P 1–4, molecular weight < 400, and polar surface area (which correlates highly with hydrogen bonding ability) <90 Ų.

As Ms Bryan pointed out in her article, efflux is a problem in BBB penetration, and some believe that crossing of the BBB is controlled largely by efflux. Using BBB penetration data obtained by the use of P-glycoprotein knockout mice, we recently showed⁵ that the role of efflux in BBB penetration could be modelled by a QSAR containing terms representing molecular size, polarity and polarisability.

We thus have considerable knowledge from QSAR about the molecular requirements for drugs to cross the BBB, and this has already aided the design of a number of CNS drugs. Clearly there is more to be done, but we are well on the way.

John C. Dearden
School of Pharmacy and Chemistry
Liverpool John Moores University

References

1. Hansch C, Bjorkroth JP, Leo A. Hydrophobicity and central-nervous-system agents – on the principle of minimal hydrophobicity in drug design. Journal of Pharmaceutical Sciences 1987;76:663–87.

2. Abraham MH, Chadha HS, Mitchell RC. Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. Journal of Pharmaceutical Sciences 1994;83:1257–68.

3. van de Waterbeemd H, Kansy M. Hydrogen-bonding capacity and brain penetration. Chimia 1992;46:299–303.

4. van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OR. Estimation of blood-brain crossing of drugs using molecular size and shape, and H-bonding descriptors. Journal of Drug Targeting 1998;6:151–65.

5. Dearden JC, Al-Noobi A, Scott AC, Thomson SA. QSAR studies on P-glycoprotein-regulated multidrug resistance and on its reversal by phenothiazines. SAR QSAR Environmental Research 2003;14:447–454.

Send your letter to The Editor

Previous Topic (Health services)
Next Topic (The Society)