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Dear all,
I have recently seen a couple of reports, where the presented data
clearly shows non-linearity in the CL of the compounds. Interestingly,
the authors apply a PK model with 2 distinctive elimination mechanisms:
a linear and a saturable.
My question is: How does one decide whether to use a single elimination
pathway (saturable CL) or two pathways (linear and saturable)? Are
there any characteristic signs in the data, that suggest 2 pathways are
necessary? Or is it just a matter of trial and error in the modeling
process that suggests the two pathway model to be superior to the one
with a single pathway?
Toufigh Gordi
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Toufigh,
The report of lazabemide PK (Guentert et al. 1994) shows it had a
classic 'non-linear' profile with single doses but with multiple doses
the predicted concentrations were lower than expected and described by
proposing an additional first-order pathway.
Guentert TW, Holford NHG, Pfefen JP, Dingemanse J. Mixed linear and
non-linear disposition of lazabemide, a reversible and selective
inhibitor of monoamine oxidase B. British Journal of Clinical
Pharmacology 1994;37:545-551.
A similar phenomenon is seen at very high doses of ethanol. The common
myth that ethanol has 'zero-order' elimination is not supported by real
data.
Holford NHG. Clinical pharmacokinetics of ethanol. Clinical
Pharmacokinetics 1987;13:273-292.
So to answer your question -- I would say that one should always have
a high index of suspicion for parallel mixed order and first order
elimination. The usual model based criteria can be applied to accept
the need for more than one pathway.
Nick
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Toufigh,
If you have data from a multiple dose study and the terminal portions
of the
Cp vs t curve for the higher doses show a shallower decline than the
lower
doses, it might be indicative of the presence of a parallel
non-saturable
pathway. The rationale is that the contribution of the parallel pathway
towards overall elimination goes on increasing (as the dose increases)
while
the other pathway remains "maxed out".You will observe this when the
saturable pathway dominates initially at low doses.
An example of such a scenario would be saturable hepatic metabolism and
parallel first order renal excretion or two parallel pathways-one with a
small Km and the other with a relatively large Km.
For the latter case please refer to the following article:
Sedman AJ, Wagner JG.
Quantitative pooling of Michaelis-Menten equations in models with
parallel
metabolite formation paths.
J Pharmacokinet Biopharm. 1974 Apr;2(2):149-60
Pankaj
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Toufigh,
A lot of the time the selection of 2 pathways, linear and saturable, is
based on underlying knowledge of the metabolism.
eg, ethanol has saturable alcohol dehydrogenase and non saturable
CYP2E1.
Susan Shoaf
Sr. Pharmacokineticist
Otsuka Maryland Research Inst.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)