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Dear,
We are currently investigating (in the rat) an anaesthetic drug
which shows zero-order kinetics in plasma. We also measure the
electroencephalographic effect as a surrogate measure of
anaesthesia. Plotting the electroencephalographic effect versus
plasma concentration results in hysteresis. Minimization of the
hysteresis in the concentration-effect relationship results in a first-
order rate constant keo. However, this procedure assumes that
drug transfer from plasma to the effect-site (= brain) is a first-
order process. We now want to find out if drug transfer through
the blood-brain-barrier is a capacity-limited process. We would
like to know if one can suspect zero-order kinetics by just looking
at the shape of the hysteresis observed in the plasma
concentration-effect curve? Which is the best method (in the rat)
to study the possibility of capacity-limited drug transfer through
the blood-brain-barrier?
Thank you in advance.
Kind regards,
Peter De Paepe, MD
Heymans Institute of Pharmacology
De Pintelaan 185
9000 Gent
Belgium
Europe
tel 0032(0)9 240 33 56
fax 0032(0)9 240 49 88
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Peter De Paepe, MD, Heymans Institute of Pharmacology wrote:
> We are currently investigating (in the rat) an anaesthetic drug
> which shows zero-order kinetics in plasma.
Beware of the zero-order assumption. A mixed order model is almost
certainly a better bet for metabolic elimination. Zero-order kinetics
only occurs at infinite concs -- so you can be sure that assumption is
wrong. Mixed-order kinetics makes more reasonable assumptions --
although "all models are wrong" the mixed order model is likely to be
more appropriate. Pure mixed order elimination is probably unreasonable
as well. There is almost always going to be some parallel first order
process(es) but this may not be detectable with single dose designs.
> order process. We now want to find out if drug transfer through
> the blood-brain-barrier is a capacity-limited process. We would
> like to know if one can suspect zero-order kinetics
Once again -- beware of assuming a zero-order model when a mixed-order
model would be a better mechanistic description of capacity-limited
transfer.
> by just looking
> at the shape of the hysteresis observed in the plasma
> concentration-effect curve?
I dont think plasma conc vs effect curve will help much. If the
collapsed effect cpt conc vs effect curve is linear then that would
suggest there was no capacity limited uptake (in the range of concs
studied). But if you see what looks a like a sigmoid emax curve then I
dont think it is easy to separate out capacity-limited transfer from an
underlying non-linear PD relationship.
> Which is the best method (in the rat)
> to study the possibility of capacity-limited drug transfer through
> the blood-brain-barrier?
You could try to measure brain interstitial fluid concs using
micro-dialysis or measure CSF concs. This should give you direct
evidence capacity-limited transfer.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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I have had a request to clarify the terminology I used in my earlier
comment on models describing rates of elimination or capacity limited
transfer across the blood brain barrier.
Zero Order: Rate=Vmax
First Order: Rate=CL*C
Mixed Order: Rate=Vmax*C/(Km+C)
IF C>>Km then Mixed Order reduces to Vmax i.e. Zero Order
If C<
Its called Mixed Order because it can be seen as a mixture between zero
and first order. The Mixed Order model has many other names e.g.
Michaelis-Menten (IMHO better reserved for enzyme kinetics), saturable,
capacity-limited, 'non-linear PK' (implicitly non-linear elimination or
concentration dependent clearance).
Parallel First Order and Mixed Order process means:
Rate=CL*C + Vmax*C/(Km+C)
'pure' mixed order was my possibly ambiguous attempt to indicate that
the only process was a mixed order process.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)