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Date: Thu, 18 Dec 1997 13:06:40 -0700 (MST)
From: Keith Anderson
cc: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Re: Apparent Bioavailability in Excess of 100%
Just a note,
A > 100% F has also been documented for colloidal delivery-
when administered iv, colloids can be taken up quickly into the organs of
the RES resulting in relatively fast clearance from plasma,however after oral
absorption, colloids (<500nm) can be absorbed and act as a resevoir for drug
delivery at a pre-capillary site or perhaps in the lymphatics as
demonstrated with some liposome systems. If the compound is hydrophobic and
forms larger "aggregates" in the iv solution this phenomenon may occur as
well...lymphatics may play a role for drugs with large partition
Date: Fri, 19 Dec 1997 12:08:35 +0200
From: bialer.-at-.md.huji.ac.il (Prof. Bialer)
Subject: Apparent Bioavailability in Excess of 100%
One possible explanation for the excess oral availabilty in a range of
150-220% is that your compound does not have a linear PK or a constant
clearance at the plasma concenration range studied.Thereofore the classical
comparison of AUCs does not hold. If you have a concenration-dependemt
clearance, it will change differntly following iv and oral administration.
One practical way to overcome this problem is to give an iv infusion which
will mimic the plasma profile obtained following oral dosing and thus,a
simlar concentration-dependent change in clearance will occur following
both iv and oral dosing.
If you wish, you could see a paper we published in that regard:M.
Bialer,W.H.Wu, Z.M.Look. B.M.Silber and A.Yacobi:Pharmacokinetics of
cefixime after oral and intravenous dose in dogs:Bioavailability assessment
for a drug showing nonlinear serum protein binding .Res. Comm. Clin
I hope this help.
Professor Meir Bialer
Dept. of Pharmaceutics
School of Pharmacy
Faculty of Medicine
The Hebrew University of Jerusalem
Ein Karem Medical Center
Jerusalem 91120, Israel
Tel: 972-2-6758610 (office) 972-2-6522405 or 972-2-6520902 (home)
Fax: 972-2-6436246 or 972-2-6784010.
Date: Fri, 19 Dec 1997 09:31:03 -0500
From: "Zutshi, Anup"
Subject: RE: PharmPK Apparent Bioavailability in Excess of 100%
Did you collect blood samples during the infusion period? Typically, if
you have a drug that has a short half-life and the duration of the
infusion is comparable to the half-life, then a significant AUC will be
lost during the infusion period, if no samples have been collected
(remember--clearance is taking place as the drug is being infused).
If this is not the case then saturable first pass metabolism could be
responsible. Thus for example if absorption from the GI tract is a rapid
process then the hepatic portal vein concentrations could be high enough
to saturate the hepatic enzymes responsible for metabolism. This would
allow a disproportionate fraction of the absorbed drug to escape into
the systemic circulation and result in elevated plasma levels and
therefore the AUC's following the oral dose.In any case, if your first
pass effects are saturated the clearance is not a constant and your dose
normalized equations for estimating the bioavailabilities is not valid.
Hope this has been helpful.
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