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Dear Members,
Does anyone know if an enterohepatic cycle may be observerd in rat
species? I've got stange results, specially a second hump in my
concentration-time curve in a drud-drug interaction PK study.
Thanks for help,
BEN REGUIGA Makrem
PharmD, PhDs
Pharmacokinetics and Clinical Pharmacy Lab.
Pharmacy Faculty - Paris XI - France
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Hello Makrem
This will be a useful reference. There could also be many reasons for
the
double peak.
A new analysis method for disposition kinetics of enterohepatic
circulation
of diclofenac in rats.
Drug Metab Dispos 1994 May-Jun;22(3):479-85
Venkatesh Atul Bhattaram
CDER, FDA.
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Enterohepatic recycling has been observed in the rat. An excellent
example is phenolphthalein. See
Colburn WA et al. A pk model for enterohepatic recycling in the rat:
phenolphthlatein, a model drug. Drug Metabolism and Disposition 7,
100-102, 1979.
Peter L. Bonate, PhD, FCP
Director, Pharmacokinetics
ILEX Oncology, Inc
4545 Horizon Hill Blvd
San Antonio, TX 78229
phone: 210-949-8662
fax: 210-949-8487
email: pbonate.at.ilexonc.com
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Hi,
Enterohepatic recirculation has been known to occur in rats and other
species. The most likely cause is the phase II conjugation of your
parent compound (glucuronidation of parent is more likely cause).
Please check the biotransformation pathway for your compound.
Sandeep
[I don't think there is a problem with the possibility of enterohepatic
recycling in the rat et al. but how is a second peak produced without a
gall bladder - db]
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Dear Makram BR,
The short answer is 'yes'. I have seen it with a number of drugs,
particularly those eliminated as glucuronides in the bile.
Derrick Parsons
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At 03:22 AM 3/26/2003, you wrote:
Does anyone know if an enterohepatic cycle may be observerd in rat
species? I've got stange results, specially a second hump in my
concentration-time curve in a drud-drug interaction PK study.
Second humps can be caused by other factors. Does your compound have
low solubility and a base pKa around 7 by any chance?
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-a-.simulations-plus.com
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Hello
It is also important to know the biotransformation of the molecule.
Also the
time of the second peak can yield important information when compared
with
average transit times in rat git. Deconjugation by the bacteria in the
lower
intestine can cause appearance of a secondary peak.
Venkatesh Atul Bhattaram
CDER, FDA.
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Absolutely. There are several papers in the literature and a quick
search should yield them. The "second peak" may not be as discernable
in rats as in humans since rats do not have a gall bladder and bile
flow into the intestine is continuous (as opposed to intermittent in
humans).
Lane
Lane J. Brunner, Ph.D.
College of Pharmacy
The University of Texas at Austin
University Station, A1920 (USPS)
2409 West University Street (courier)
Austin, TX 78712-0126
Tel: (512) 471-0942
Fax: (512) 471-7474
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We have collected rat bile and re-injected in guts of un-dosed rats to
study enterohepatic circulation. Glucuronosyl conjugates from bile are
hydrolyzed in the gut and the aglycone (parent drug) re-absorbed.
Sandeep
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Dear Walt Woltosz
I've not given precison about the compound because the observation I
madeoccured twice with two different compounds; The first is digoxin,
the second is a compound in devlopment which have nearly the same
properties (chemical and physical properties) than digoxin....
Thnak you for your help
BEN REGUIGA Makrem
PharmD, PhDs
Pharmacokinetics and Clinical Pharmacy Lab.
Pharmacy Faculty - Paris XI - France
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At 01:41 PM 3/26/2003, you wrote:
I've not given precison about the compound because the observation I
made occured twice with two different
compounds; The first is digoxin, the second is a compound in
devlopment which have nearly the same properties
(chemical and physical properties) than digoxin....
I see. But I could imagine that the two may have entirely different
reasons why they show double peaks. We see a double peak with
saquinavir in human that some have thought was due to enterohepatic
circulation, but we duplicate it almost perfectly in simulation without
using enterohepatic circulation or food effects. It has low solubility
and a base pKa a little over 7 that (in our simulation) causes
precipitation at the higher pH in ileum, but the subsequent lower pH in
caecum causes a marked improvement in solubility.
So you might say the precipitation in the ileum causes a single trough,
rather than a double peak.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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Dear all,
I am curious to know under what circumstances will a drug interaction
lead to
triggering of enterohepatic recycling (EHR) when it is not seen in the
concentration time profile of the drug when administerd alone. It is
usually
observed that the EHR is disrupted by drug-drug interactions, the
popular ones
being with oral contraceptives such as Ethinyl estradiol and
antibiotics such
as Ampicillin/Tetracycline.
Thanking in advance sor the suggestions
Raj
Rajanikanth M
Post Doc Assoc
Pharmaceutics Division
University of Florida
Gainesville
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Dear All, I think the traditional thought for most of us has been that
the double peak phenomomenon is through EHR.I think that one should
consider, as is the case with ALP (Alprazolam after PO) that the
mechanism underlying the double-peak phenomenon may be due to the
reduction in gastric motility caused by the muscle relaxant effect of
ALP.In addition, check to see the drugs you are co-admin and also
yours if it has any muscle relaxant effect.Also I am assuming that you
are administering it Oral.If oral, have you looked at your IV profile?
Any double-peak?
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