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Does anyone have experiences/observations of multiple peaks in the
conc-time profiles following oral dosing both from a modeling
perspective as well as mechanistic ideas. Since the model is the rat,
can enterohepatic recirculation be ruled out. Also any ideas on testing
the hypothesis of discontinous absorption or absorption from multiple
sites in the GIT.
Thanks,
Sara Kenkare Ph.D.
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[A few replies - db]
Date: Mon, 4 Oct 1999 00:49:05 -0700 (MST)
X-Sender: ml11439.-at-.pop.goodnet.com
To: PharmPK.-at-.boomer.org
From: ml11439.at.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK multiple peaks in oral profile
Hello Dr.Kenkare,
One possiblity that you didn't allude to in your question involves
the formation of insoluble complexes in the GI tract by the drug being
absorbed. Phenytoin when given in very large oral doses will form complexes
in the GI tract which retard absorption, and may result in mutiple peaks.
Mike Leibold, PharmD, RPh
ML11439.-a-.goodnet.com
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Date: Mon, 4 Oct 1999 10:22:44 +0200 (MET DST)
From: Maria Durisova
To: PharmPK.at.boomer.org
Subject: Multiple peaks in oral profile
From a modeling perspective I can recommend you our papers:
1. L.Dedik, M.Durisova, New general formulas for estimation of
mean residence time and its variance, Pharmazie, 52, 1997,
404-405.
2. M.Durisova, L.Dedik, Modeling in frequency domain used for
assessment of in vivo dissolution profile, Pharm. Res., 14,
1997, 860-864.
Study (1) presents an example of modeling a conc-time profile
with two significant peaks. Modeling procedure used in this
study is general and can be employed for conc-time profiles
with multiple peaks.
Study (2) describes an example of modeling the influence of
the gastric emptying rate on drug absorption.
Best regards,
Maria Durisova
Institute of Experimental Pharmacology
Slovak Academy of Sciences
SK 842 16 Bratislava, Slovak Republic
Phone/Fax: 0042 5477 5928
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From: "Pardue, Roseline"
To: "'PharmPK.aaa.boomer.org'"
Subject: RE: PharmPK multiple peaks in oral profile
Date: Mon, 4 Oct 1999 15:05:57 +0200
There are three research papers on discontinous absorption after oral
administration.
They are as follow:
1. Use of a pharmacokinetic model incorporating discontinuous
gastrointestinal absorption to examine the occurrence of double peaks
in oral concentration-time profiles. Pharmaceutical Research, Vol. 9, No.
3, 350-356, 1992.
2. Discontinuous oral absorption pharmacokinetic model and
bioavailability of 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)
uracil (L-FMAU) in rats. Biopharmaceutics & drug disposition, Vol. 17,
197-207, 1996.
3. Applications and simulations of a discontinuous oral absorption
pharmacokinetic model. Pharmaceutical Research, Vol. 13, No. 11,
1720-1724, 1996.
Hope this helps.
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From: "Melethil, Srikumaran K."
To: "'PharmPK.-at-.boomer.org'"
Subject: RE: PharmPK multiple peaks in oral profile
Date: Mon, 4 Oct 1999 09:46:32 -0500
Dear Dr. Kenkare,
Rats have a greater tendency to excrete drugs in the bile; so, enterohepatic
circulation (EHC) is a possibility. In that connection, what is the MW of the
drug? Drugs with MW greater than 300 are likely candidates for biliary
excretion, and perhaps EHC.
In principle, one can model oral Cp profiles with different ka values if some
indication is available reg: residence times at each of the absorption sites.
Sri Melethil, Ph.D.
Professor of Pharmaceutics and Medicine
University of Missouri-KC
School of Pharmacy
Room 203-B, 5005 Rockhilll Road
Kansas City, MO 64110
816-235-1794 (fax: 816-235-5190)
---
X-Sender: blument1.aaa.pop.niehs.nih.gov
Date: Mon, 04 Oct 1999 13:12:02 -0400
To: PharmPK.at.boomer.org
From: Greg Blumenthal
Subject: Re: PharmPK multiple peaks in oral profile
1) Rats exhibit enterohepatic recirculation of many chemicals.
2) Absorption from multiple sites in the GI tract at different rates
very possible.
I am interested in any ideas about determining absorption rates
independently. They are often crucial components in PBPK models of
orally dosed compounds.
Greg Blumenthal (blument1.at.niehs.nih.gov)
TEL: 919-541-7791, FAX: 919-541-1479
MD A3-06, NIEHS, P.O.Box 12233, RTP, NC 27709-2233 USA
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X-Sender: landoni.at.fcv.medvet.unlp.edu.ar
Date: Mon, 04 Oct 1999 16:19:18 -0300
To: PharmPK.-at-.boomer.org
From: Fabiana Landoni
Subject: Re: PharmPK multiple peaks in oral profile
Dear Sara:
Have you fasted the animals for some hours previuos administration?. We
have seen multiple peaks after oral administration of NSAIDs in not fasted
horses and it was related with the binding of drug to the feed. The
observed peaks are reflection of the fermentative digestion of feed in the
large intestine and the release of the bound drug.
I hope it helps you
Fabiana
Prof. Dra Maria Fabiana Landoni, PhD
Catedra de Farmacologia.
Facultad de Ciencias Veterinarias
Universidad Nacional de La Plata
FAX +54-221-425-7980
Calle 60 y 118 cc 296
(1900) La Plata.
ARGENTINA
---
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Our recently published paper may answer some of your questions.
Title: A double-peak phenomenon in the pharmacokinetics of alprazolam
after oral administration. Drug Metabolism and Disposition 27:
855-859, 1999.
Chyan Elinore Lau, Ph.D.
Department of Psychology
Rutgers University
Piscataway, NJ 08884
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Dear All
Ref: Multiple peaks ...
In one of my early papers Wu G. Fit fluctuating blood drug
concentration: a beginner=92s first note. Pharmacological Research 1996;
33: 379-383=92, I have shown that the analytical solution of multiple
compartmental model is
C(t) =3D sum j from 1 to q Aj exp(-Mj t) + sum k from 1 to r exp(-Nk
t)cos(Pk t + Qk)
rather than
C(t) =3D sum i from 1 to n Ai exp(-Mi t)
With the decaying cos function, the blood concentration can have several
decreasing peaks.
As no-one is interested in this work, this equation had already been
buried in my memory, if you have a little interest, it will reward me a
lot.
With the deepest respect.
Guang Wu, MD, PhD
Istituto di Farmacologia Clinica e Tossicologia
Cattedra di Farmacologia Speciale
Facolt=E0 di Medicina e Chirurgia
Universit=E0 degli Studi di Udine
Piazzale Santa Maria della Misericordia
I-33100 Udine
Italy
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It seems that double peaks could have several root causes, such as:
(1) Regional absorption differences caused by pH dependence of permeability.
(2) Regional absorption differences caused by transporter densities for
actively transported drugs.
(3) Regional solubility differences due to pH dependence.
(4) Regional efflux differences due to density of effluxing proteins.
There are references in the literature for ranitidine and cimetidine, for
example, that indicate that the double peaks seen in Cp-time data for these
drugs are caused by differences in absorption. Both drugs have base pKa's
around 7, so solubility would be expected to decrease significantly as the
drug moves from duodenum (at about pH 6) to distal ileum (at about pH 7.5),
and then increase again in cecum (at about pH 5). As the drug moves into
the ascending colon (pH>7) the solubility should drop again. The time of
the second peak (4-6 hours) coincides with the expected arrivial time in
cecum, although there has been some conjecture that ranitidine and
cimetidine are not well absorbed in colon.
Interestingly, as solubility decreases due to pH and the pKa's of the drug,
one might expect permeability to have an inverse relationship. The problem,
therefore, is not a simple one.
It seems that without considerably more information, the specific mechanism
for double peaks cannot be gleaned from Cp-time data alone.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 West Avenue J
Lancaster, CA 93534-2902
U.S.A.
Phone: (661) 723-7723
FAX: (661) 723-5524
http://www.simulations-plus.com
walt.aaa.simulations-plus.com
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From: "Bruce CHARLES"
Organization: School of Pharmacy
To: PharmPK.-a-.boomer.org
Date: Wed, 19 Oct 1999 16:07:16 +1000
Subject: Re: multiple peaks in oral profile
X-Confirm-Reading-To: "Bruce CHARLES"
X-pmrqc: 1
Priority: normal
I don't know what others have said before in response to this but
what about "dose dumping" from the stomach as a possible
explanation of double peaks?
Cheers,
BC
Bruce CHARLES, PhD
Senior Lecturer
Director, The Australian Centre for Paediatric Pharmacokinetics
University of Queensland, School of Pharmacy, QLD 4072
Australia
+61 7 336 53194 (TEL)
+61 7 336 51688 (FAX)
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Date: Tue, 19 Oct 1999 09:13:44 -0400
From: "Sreevatsa Natarajan"
Organization: PPD
X-Accept-Language: en
To: PharmPK.aaa.boomer.org
Subject: Re: PharmPK Re: multiple peaks in oral profile
Here's my 2 cents worth on the problem of double peaks:
(a) As Dr. Waltosz pointed out double peaks could also be caused
by recycling
of the drug by regional distribution differences of active absorption/efflux
proteins in the gut. Thus a drug molecule could potentially be absorbed in the
proximal portions of the gut (Stomach, Duodenum) be picked up by the efflux
proteins along the gut wall and secreted in the distal portions of the gut
(ileum) and be reabsorbed again in the colonic segments. While most drugs are
passively transported and hence not effectively absorbed in the
colonic segments
due to tighter junctions, some drugs are prone to colon specific absorption
mechanisms. But these mechanisms are complex and is very drug-specific and more
info. on the drug and the transport protein(s) is necessary before one can
arrive at this conclusion.
(b) Another possible reason for this could be renal tubular reabsorption of the
drug.
(c) Certain metabolic reactions are purportedly reversible and could possibly
contribute to this observation too. However, a specific example does not
immediately come to mind.
Hope that helps,
Sreevatsa Natarajan (Vatsa)
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