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Could you kindly explain, why a compound when dosed p.o gives 10
times longer half-life over the i.v half-life. Am I right that
slow rate of absorption is giving us a longer half-life in p.o.
dosing.
What causes this increase in half-life after p.o. dosing; I agree
that Flip-Flop i.e. non-parallel curves (i.v and p.o.) mean terminal
phase in p.o. curve is absorption.
So is it absorption rate limited elimination.
Kind regards
M. Yaqoob
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The following message was posted to: PharmPK
Dear M. Yaqoob,
apart from flip-flop, and even if 10 times represent un unexpected
difference, I suggest two possible additional causes of terminal half life
differences after p.o and i.v. diosing
1- The first possible cause is the enterohepatic circulation of unmodified
compound. This is usually a possible confounding occurrence in half life
estimation and, if enough points during elimination phase are available, a
sinusoidal-like profile is usually expected. This phenomenon is commonly
encountered during preclinical pharmacokinetics and toxicokinetics studies
where high oral doses are used, even if some examples occur in clinical
pharmacology practice too.
2- The second possible cause is the large extent of distribution after
intravenous administration that can directly lead to very low amounts of
compound during the elimination phase after intravenous dosing. This
occurrence usually provides as direct consequence the incorrect estimation
of the elimination phase (underestimated) that is still made up of
distribution and elimination components. This occurrence is not usually
evident after oral dosing when distribution kinetics are covered by
absorption processes.
Best regards
Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
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The following message was posted to: PharmPK
Dear M. Yaqoob,
I apologize I have forgotten a well-known possible reason of higher half
life after oral dosing: the unexpected inhibition of major clearance pattern
when similar inhibition does not occur after intravenous dosing. This
typically happens when different doses or formulations are used, expecially
in animal preclinical studies.
An example of a common pattern is the irreversible saturation of liver
oxidative metabolism by mechanism based inactivation of the specific
principal P450. After oral dosing it's easier to inhibit liver enzymes, as
regards to intravenous dosing, because of higher compound concentrations in
portal vein. If this is the occurrence, after first pass irreversible
inhibition of a major clearance enzyme you expect a reduced total clearance
of compound and this pattern is confirmed without difficulty by increase of
plasma half-life.
Best Regards
Stefano
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The following message was posted to: PharmPK
Dear M. Yaqoob,
Yes, your long oral t1/2 is due to absorption rate limited elimination.
This is a very common finding in discovery research. The reason is
usually that your research grade oral formulation is not optimized. The
compound is probably in a suspension (or becomes a precipitate shortly
after dosing) and leads to crystals and aggregates of test article
remaining in the GI tract for extended periods of time. This extended
absorption is giving you your long oral half-life, and it generally has
nothing to do with any effect on drug clearance. Test several different
oral formulations and you will probably see large changes in oral t1/2.
Peter Rix
Ligand Pharmaceuticals, Inc.
San Diego, CA
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