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Hello dear all,
Has anyone information about the distribution of (specially) naratriptan
and zolmitriptan. Do both drugs pass the blood brain barrier in greater
extend than sumatriptan?
Erik Pomp
erik.pomp.-at-.haukeland.no
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Erik,
You may have a look at a paper by Goatsby, which showed specific binding of
nara and zolmi. However, remember that passage during a migraine attack may
be different from it is can be in lab animal or human outside of an attack.
Eliane
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EriK:
I would echo Elaine's comment about different distribution during
migraine attacks from outside them, particularly delayed gastric
emptying. This will increase the proportion "lost" to the first pass
effect, for one thing, besides reducing Cmaxs. I wouldn't expect it to
reduce the proportion bound to plasma proteins, though.
Andrew Sutton
Guildford Clinical Pharmacology
Andrew Sutton
Guildford Clinical Pharmacology
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Eliane and Erik,
I find the PK characteristics of the class of drug are very interesting
because their bioavailability and therefore efficacy may well be affected
by the predictable delay in gastric emptying during migraine (See Boyle R
et al Br J Clin Pharmacol, 1990 30 405-409) but I have not seen it
quantified anywhere. I suppose this is partly because the parenteral
route is usually used where there is doubt about absorption.
The loss of efficacy would depend on the proportion of dose which is
active (ie: after saturating binding sites etc.) So whilst I would be the
first to accept data showing that Naratriptan has a low first pass
effect, from your figure of 70% available there is still 30% to account
for, so I would be intrigued if you have or know of data on where it
goes.
The size of the effect could be studied for the whole class of drugs if
we could slow gastric emptying in volunteers (eg: by morphine, see Murphy
DB et al Anesthesiology, 1997, 87: 765-770) and assess bioavailability in
the usual way. We would measure gastric emptying at the same time to
examine the correlation between it and any effect....
Andrew Sutton
ASutton.at.gcpl.co.uk.
Andrew Sutton
Guildford Clinical Pharmacology
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I would expect delayed gastric emptying to affect absorption rate/extent but
not affect distribution. Can Eliane clarify if she was referring to changes
in distribution (e.g. as described by inter-compartmental clearance and
volume of distribution) or to changes in absorption or perhaps both?
--
Nick Holford, Center for Drug Development Science
Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197
email:n.holford.aaa.auckland.ac.nz tel:(202)687-1618 fax:687-0193
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Nick:
We showed differences in Ka between oral administration of naratriptan 2.5mg
during an attack and in a pain free period, which resulted in a moderate but
significant difference in Cmax. There was no difference at all in Cl/F ( no
diff in AUC) (ref COST B1 meeting, Geneva 1997). Distribution of naratriptan
into a peripheral compartment is only observed with parenteral
administrations, with a small V1compared to Vss: using pop modelling and
historical data, we did not find any difference in volumes between patients
treated during an attack with sub-cut naratriptan and healthy subjects
(paper accepted by European Journal of Neurology).
"Distribution" in brain or passage through BBB could be modified during a
migraine attack due to blood flow changes, but the amount would not affect
PK profile in serum/plasma: this is an hypothesis based on the differences
in animal tissue/receptors binding in brain observed between all triptans
with anti-migraine activity in man (Goadsby paper).
Eliane
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