HiBack to the Top
Has anyone any idea if a brain/plasma concentration ratio of 100:1 for a
drug at steady state is unusual?? I would be very grateful if someone
could
direct me to a reference of brain/plasma ratios for drugs already on the
market as my search of the literature has not been very fruitful!!
David Jones
Dept. of Bioanalysis
NeuroSearch
Denmark
From my (limited) experience a ratio of 100:1 would certainly be on theBack to the Top
high end of the scale; imipramine, which readily crosses the BBB
achieves values in the region of about 50:1.
I am afraid I can't help you on the reference front.
Regards,
Nick Kerwin,
Head of In-Vivo Discovery
BioDynamics Research Limited
Hi All,Back to the Top
I also have a question regarding plasma csf and brain levels of the
drugs.
I normally calculate the brain levels in ng of the compound/g brain.
CSF and Plasma ng/ml, when you say the ratio, is it a concentration
ratio between plasma and CSF, or do I need to calculate how much plasma
and CSF in a rat then calculate the ratio.
Second question:
Nicholas Kerwin mentioned the ratio of 100:1 of plasma to brain, I was
not clear how to calculate the ratio, because I normally calculate the
brain concentraion as ng/g brain and plasma as ng/ml.
Third:
I working in the drug development of R&D and we are screening the
compounds doing in vivo permeability in brain and CSF, what is the
optimum(ratio) value for a good candidate for neuro drugs.
Thanks
Lourdes
David,Back to the Top
The following article may be useful to you:
Iyer M, Mishru R, Han Y, Hopfinger AJ. Predicting blood-brain barrier
partitioning of organic molecules using membrane-interaction QSAR
analysis. Pharm Res. 2002 Nov;19(11):1611-21.
Best regards,
Jackie
HiBack to the Top
Baclofen (Lioresal TM), is a typical drug with brain/plasma ratio >100,
you can find references from different authors : Kroin, 1991 book
chapter in: parenteral drug therapy in spasticity and parkinson
desease; M\0xB8ller and Ziersky book chapter in : Local spinal therapy of
spasticity 1988, Penn 1987 lancet, Sallerin-cautes aur j clin pharmacol
1991, Knutsson J neurol Sci 1974, Deguchi pharm res 1995 etc...
I hope this will help you
Fr\0xC8d\0xC8ric Lagarce
Inserm eritM0104
Angers, France
David Jones asked if a brain/plasma concentration ratio of 100:1 for aBack to the Top
drug at steady state is unusual and remarked that it is difficult to
find data.
I wonder if you have tried searching the anaesthetic literature as this
subject has long interested the anaesthetic fraternity. I found some
interesting references by a Google advanced search including all the
words: Anaesthetic, Concentration, CSF, Pharmacokinetics.
For example: Dawidowicz A. L. reported a 50 : 1 ratio of blood to CSF
for propofol the iv anaesthetic. [Cerebrospinal fluid and blood
propofol concentration during total intravenous anaesthesia for
neurosurgery British Journal of Anaesthesia, 2003, Vol. 90, No. 1
84-86.] Given the high lipophilicity of propofol this makes your 1:100
ratio look very unusual indeed.
The same authors have also published on free and bound ratios since
that does change the picture somewhat.[ Dawidowicz AL et al (2003)
Free and bound propofol concentrations in human cerebrospinal fluid.
British Journal of Clinical Pharmacology Volume 56?Issue 5?Page 545.]
In their 1st group of patients the mean (and 95% confidence interval)
total plasma propofol concentration was 6113 (4971, 7255)?ng?ml1, the
mean free propofol concentration in plasma was 63 (42, 84)?ng?ml1, and
the mean total propofol concentration in CSF was 96 (76, 116)?ng?ml1 (
P?I hope this helps. I have not tried to search using the American
spelling of anaesthesia but that should be quite productive.
Andrew Sutton
dear davidBack to the Top
I'm afraid I wasn't reaaly awake this morning!
in fact the brain/plasma ratio of baclofen is <0.01 if the drug is
given by oral route and >10 if the dose is given intrathecally. This
drug remain in the CSF, its CSF clearance is much lower than its plasma
clearance. If you inject the drug by oral route, less than 1% will
reach CSF but if you inject the drug by intrathecal route it will
remain in the CNS, and you'll find very small amounts in the plasma as
its clearance is consequent.
So, after reading you question again, I don't think baclofen is a
perfect drug for your studies.
Frederic Lagarce
We have tested hundreds of novel/generic, effective CNS/peripheralBack to the Top
targeted
compounds via single dose oral and/or iv dosing during the past several
years and the highest B/P ratio we had found so far is less than 10. The
value was obtained by a simple ratio of concentrations (ng/g)/(ng/mL),
assuming that d=1 for brain tissue. We found, in general, that B/P
ratio is
somewhat related with LogD value, a logical conclusion. It is not
likely
that any compound with a LogD value near 100 will have any
pharmaceutical
value. The drug concentration in brain should be in some kind of
equilibration with the drug concentration in plasma at steady state.
Barring any special transport mechanism was involved, I would recommend
that
you may want to re-check your bioanalytical method and data to make
sure the
calculation is correct. If the bioanalytical is correct, you may need
to
concern about long term toxicities in brain and other target organs.
Ta Kung Chen, Ph.D.
Associate Director, Pre-Clinical Development
Neurocrine Biosciences, Inc.
10555 Science Center Rd.
San Diego, CA 92130, USA
Phone: 858 658-7726
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