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The following message was posted to: PharmPK
Dear all,
I would like to know if an enterohepatic recirculation may
be considered responsible for an AUC greater after oral than after iv
administration of the same dose of a drug? If so, could you suggest me
any references?
Thank you in advance
--
Dr. Federico Pea, MD
Clinical Pharmacologist
Institute of Clinical Pharmacology & Toxicology
Medical School
University of Udine
P.le SM Misericordia, 3
33100 Udine
Italy
email: federico.pea.-a-.med.uniud.it
URL:http://www.uniud.it/ifct/welcome.html
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[A few replies - db]
From: "Armin Bruelisauer"
Date: Thu, 22 Feb 2001 20:41:26 +0100
To: david.at.boomer.org
Subject: Re: PharmPK Biovailability >1
The following message was posted to: PharmPK
Dear Dr. Pea,
in my opinion, enterohepatic circulation seems unlikely (occurs after both
rotes of administration).
What about saturated first-pass? This may be indicated by higher
blood/plasma levels after the oral dose.
Best Wishes
Armin Bruelisauer
Basel, CH
---
From: Nick Holford
Date: Fri, 23 Feb 2001 08:56:01 +1300
To: david.-a-.boomer.org
Subject: Re: PharmPK Biovailability >1
The following message was posted to: PharmPK
Consider this:
Rate out = Clearance x Conc
The integral of Rate out wrt time from 0 to infinity is F x Dose.
The integral of Clearance x Conc is Clearance x AUC therefore:
F x Dose = Clearance x AUC
The only assumption here is that elimination is constant clearance
(i.e. first order). If clearance from the central compartment is the
same for IV as it is for oral then AUC oral must be less than AUC IV
if F<1.
Enterohepatic recirculation is no different in kinetic terms from a
drug moving from the central compartment to a peripheral compartment
and back again.
If it is observed that AUC oral is greater than AUC IV (and assuming
that the AUC is properly extrapolated to infinity) then this points
to a non-first order process. The best known example of this
phenomenon is for ethanol which has mixed order elimination and
saturable first-pass extraction. Rapid oral absorption of the same
ethanol dose can have a greater AUC than the same dose given IV if
the IV infusion is relatively long in duration so that peak oral
concs are greater than peak IV concs.
--
Nick Holford, Divn 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)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
From: David Jaworowicz
Date: Thu, 22 Feb 2001 15:07:47 -0500
To: david.aaa.boomer.org
Subject: Re: PharmPK Biovailability >1
The following message was posted to: PharmPK
Dr. Pea,
I believe it is possible that enterohepatic recirculation can be responsible
for greater AUCs after an oral dose compared to an iv administration of the
same dose. This is much more likely for larger MW compounds that are
rapidly and completely absorbed. Many drugs that undergo phase II
glucuronidation and are secreted into bile are then hydrolized back to the
parent compound inside of the gut by beta-glucuronidase enzymes and then
this parent is reabsorbed.
Evidence of recirculation can be found in the plasma concentration-time
curve. A small secondary peak following the Cmax suggests enterohepatic
circulation. It should be noted that biliary excretion is a saturable
process and if very large or multiple doses are being administered orally,
the reabsorption process may influence actual absorption and/or the
elimination rate constants, affecting the plasma concentration-time curve.
Keep in mind though that there are other possible reasons for an oral AUC
being higher than an iv AUC. These are particularly due to the experimental
methods rather than actual PK. For example, problems with drug solubility
and precipitation within the iv dosing vehicle may result in the
administration of a lower iv dose, etc.
Sincerely,
David Jaworowicz, Jr.
Research Associate
Cognigen Corporation
Williamsville, NY
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The following message was posted to: PharmPK
From:
Kazimierz H. Kozlowski, Pharm.D.
Laboratory of Clinical Pharmacology
The Childrens Memorial Health Institute
04-736 Warsaw, POLAND
E-mail: khkoz.-a-.czd.waw.pl
Dear Dr Pea,
There are not rare examples of drugs possesing extra-AUC
after extravascular administration: glycoprotein-P mechanism
in drug-transport, effective-half-life in apparent disposition,
self-inhibition in liver drug-metabolizm, protein-binding
mechanizm, bio-discrimination for optical izomers, native drug
or metabolite pharmacodynamics, ingradients in oral preparate
(grapefruit-juice) etc.
It is interesting if t1/2 is prolonged after oral
route?(example-erythropoetin after s.c).
Article could be also help: Peris-Ribera J.E. et al.:
General treatment of the enterohepatic recirculation of drugs
and its influence on the area under the plasma level curves,
bioavailability, and clearance. Pharm. Res. 9,1306-13,1992.
(describing the effect of enterohepatic recycling on AUC and
bioavailability of drugs).
Sincerely
Kazimierz H. Kozlowski
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)