PharmPK Discussion - Non-linear PK?

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On 29 Aug 2002 at 23:41:16, "James J. Wang" (jamesjwang.aaa.eudoramail.com) sent the message


Dear colleagues:

I dosed a compound to mice (N=3) at 5 and 50 mg/kg.  V and Cl
decrease significantly (~10X) from low to high dose.  However, the
t1/2 are the same for both dose levels. The plasma conc.-vs-t
profiles (after dose normalization) are paralle but do not fall
together.  I can undersatnd the change in apparent Cl when the
metabolism capacity is saturated at high dose, but why V also changes?

Your explanation/suggestions would be highly appreciated.

James J. Wang, Ph.D.
Senior Research Scientist II
MethylGene Inc.
7220 rue Frederick-Banting
Montreal, Quebec
Canada H4S 2A1

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On 2 Sep 2002 at 09:07:42, keith.t.muir.at.gsk.com sent the message


James:

Are you giving the drug orally?  If so, you are estimating V/F and
Cl/F (not V and Cl).  If F increases with dose due to, for example,
saturable first pass metabolism, then this might explain your
observation.  For a high clearance drug, T1/2 would not be expected
to change.

Regards

Keith

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On 4 Sep 2002 at 12:49:59, "James J. Wang" (jamesjwang.-at-.eudoramail.com) sent the message


Hi, Keith and everybody:

I did both i.v. and p.o. at two doses, low and high (10x).  The same
phenomena were observed for the two routes.  Both t1/2 and F are
about the same for the two doses.  I start to think this might be
caused by saturable tissue distribution.  This will explain the
change in V.  But not in Cl.  Do I have two mechanisms going on,
saturable tissue distribution and saturable metabolism at the same
time?

Still thinking hard,

James J. Wang

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