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Dear All:
When we establish a PBPK model for intestinal absorption, we often use
many first order constants (Ka) for drug transferring among different
compartments, such as lumen, gut wall or mucosal enterocytes, serosa,
portal vein, etc.. We know that the Ka value between lumen and gut wall
can be calculated from Caco-2 permeability data (Apical to basolateral
or Basolateral to Apical). But how to get the other kinds of Ka values
between other compartments such as gut wall and portal vein or mucosal
enterocytes and serosa described in the segregated-flow model?
Jian
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The following message was posted to: PharmPK
Dear Jian,
You said, "We know that the Ka value between lumen and gut wall can be
calculated from Caco-2 permeability data".
No, we do not. You can estimate a permeability, but that does not give you
Ka. Even permeability is only a rough estimate at best, usually calculated
by comparing human jejunal permeability from the BCS compounds to the Caco-2
data for the same compounds to get a conversion equation - which only
applies in the jejunum where the BCS Peff values were measured. Take a look
at the variance in the human Peff measurements, then at the variance in
Caco-2 measurements, and you'll see that it's far from an exact
relationship.
Using a constant Ka is an approximation that is always incorrect. Sometimes
you can get away with it, but usually you don't know if you can for a
particular compound unless it has both high permeability and high solubility
and is absorbed quickly in the proximal small intestine with no
rate-limiting dissolution or solubility effects.
In general, Ka is a coefficient, not a constant (Amidon). It varies with
time and location. If you want to calculate oral absorption in a manner
closer to reality, you need to account for the differences in local
conditions along the intestinal tract - changing pH, changing surface areas,
changing tight junctions in the case of paracellular transport, changing
concentration in the lumen and enterocytes, and so on.
Fick's First Law calculates mass transfer across a membrane as a function of
the concentration gradient, i.e., the difference in lumen and enterocyte
concentrations in this case. Clearly these change with time. In fact, for
passive diffusion, if the concentration in the enterocytes becomes equal to
the concentration in the lumen, passive diffusion stops because there is no
driving force (Ka = 0!). A constant Ka ignores this important factor.
You state you're using a PBPK model - I'm surprised that you would have the
sophistication of a PBPK model for pharmacokinetics and use an
oversimplified model for absorption. GastroPlus(tm) provides all you need to
get it all right. I believe SimCYP and PK-Sim also have better oral
absorption models than constant Ka, but I have not seen their equations.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Hi Jian
Although from a pure mathematical view these are rate constants (of
course not necessarily they are all constant) but in the PBPK context
they may have different meaning form one another. Anyway, if you are
referring to the segregated-flow model developed by the Sandy Pang's
group then their publications are the best place to find the definitions
e.g.:
Chow ECY, Durk MR, Cummins CL and Pang KS (2011) 1\0x03B1,25-Dihydroxyvitamin
D3 Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not
Farnesoid X Receptor in Both fxr(-/-) and fxr(+/+) Mice and Increased
Renal and Brain Efflux of Digoxin in Mice In Vivo. Journal of
Pharmacology and Experimental Therapeutics 337:846-859.
Pang KS and Durk MR (2010) Physiologically-based pharmacokinetic
modeling for absorption, transport, metabolism and excretion. J
Pharmacokinet Pharmacodyn 37:591-615.
Fan J, Chen S, Chow EC and Pang KS (2010) PBPK modeling of intestinal
and liver enzymes and transporters in drug absorption and sequential
metabolism. Curr Drug Metab 11:743-761.
Regards
Masoud
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Dear Walt:
Thanks for your kindly response. I know that the better way to estimate oral absorption
is to seperate intestines into several parts such as duodenum, jejunum, and ileum,etc, and
at the same time considering the different physiological properties of each part (pH,
length, transit rates, P-gp abundance) into the estimation. But what I studied now is a
compound with high permeability and high Fa (>95%), so I think I can simplify this
absorption model with a constant Ka. What I am regarding is its potential P-gp efflux,
which maybe effect its residence time and metabolism in enterocytes. I want to seperate
the absorption site into lumen, enterocytes in mucosa, serosa, etc., but can not be sure
how to get the transfer rate values between these compartments.
Jian
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The following message was posted to: PharmPK
Dear Jian,
You said: "I know that the better way to estimate oral absorption is to
separate intestines into several parts such as duodenum, jejunum, and ileum,
etc, and at the same time considering the different physiological properties
of each part (pH, length, transit rates, P-gp abundance) into the
estimation. But what I studied now is a compound with high permeability and
high Fa (>95%), so I think I can simplify this absorption model with a
constant Ka. What I am regarding is its potential P-gp efflux, which maybe
affect its residence time and metabolism in enterocytes. I want to separate
the absorption site into lumen, enterocytes in mucosa, serosa, etc., but
cannot be sure how to get the transfer rate values between these
compartments."
Your statement implies that you want to look at absorption as a single
absorbing compartment with separate lumen, enterocytes, etc. for the purpose
of examining potential P-gp efflux. However, with P-gp it is just as
important to separate the intestinal tract into at least its major absorbing
regions (duodenum, jejunum, ileum, caecum, colon) because the expression
levels of P-gp in each region are different. On the other hand, if your drug
is truly high permeability and high solubility, it may be mostly absorbed in
jejunum, so there may not be much influence due to the change in the P-gp
expression in the ileum and colon.
In general, calculating in vivo carrier-mediated transport using
Michaelis-Menten kinetics requires fitting the Vmax to in vivo data - there
is not yet a good way to estimate in vivo parameters from in vitro
measurements. Values for in vitro Km can be used in GastroPlus to model the
nonlinear dose dependence for substrates of influx transporters, but Km for
Pgp substrates must be fitted to in vivo data (Bolger et al., AAPS Journal,
11(2):353, 2009).
In our experience, P-gp is relatively easy to saturate in vivo for most
drugs, especially those that are absorbed quickly in the proximal small
intestine. If you're lucky, you may find that P-gp efflux is not significant
for oral absorption in vivo, even if the B-A/A-B ratio in vitro indicates
efflux.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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I thought that "high permeability" meant by definition that transporter effects would not
be observable on the compound, even if it was a substrate.
On the other hand, effects of the compound on the transport of other substrates might well
be observed.
Am I missing something?
Thanks,
Rachel
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The following message was posted to: PharmPK
Dear Jian
This very recent paper may be of help.
Int J Pharm. 2011 Oct 14;418(2):161-7. Epub 2011 Apr 8.
Estimation of Michaelis-Menten constant of efflux transporter
considering asymmetric permeability.
Sugano K, Shirasaka Y, Yamashita S.
Regards
David Turner
Simcyp Limited
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Hi Rachel
Your expectation that high permeability often means no or limited
transporters effects is by and large correct, however one can't provide
an accurate and quantitative answer unless all (or at least most)
contributing elements are incorporated in a suitable model.
We have used the ADAM model (please see:
http://www.pharmagateway.net/ArticlePage.aspx?DOI=10.1208/s12248-009-
9099-y) to look at the relative roles of P-gp-mediated efflux and
passive permeability for digoxin, quinidine and talinolol (please see:
http://www.simcyp.com/UploadedFiles/291/Neuhoff_2009_LogP_absorption.pdf
).
Also, we have studied the interplay of metabolism and transport in a
range of hypothetical (but in realistic ranges) compounds, please see:
Darwich AS, Neuhoff S, Jamei M and Rostami-Hodjegan A (2010) Interplay
of Metabolism and Transport in Determining Oral Drug Absorption and Gut
Wall Metabolism: A Simulation Assessment Using the "Advanced
Dissolution, Absorption, Metabolism (ADAM)" Model. Curr Drug Metab
11:716-729
(http://www.ingentaconnect.com/content/ben/cdm/2010/00000011/00000009/art00002).
Regards
Masoud
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Dear walt:
Many thanks for your help. Now I am trying to use seperate absorbing
compartment to re-establish my PBPK model. But another problem I met is
if we seperate intestines into seven compartments, I can not find the
corresponding values of enterocyte volume (Vent,n) for each compartment.
Can you provide me these values? I read a lot of papers about intestinal
absorption model, but can not find any information about this kind of
data. Thanks!
Jian
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The following message was posted to: PharmPK
Dear Jian
We, at Simcyp, have values for Vent. These are built-in to the simulator
and are viewable (and modifiable) by users of the software.
Please contact me off-line if you would like to discuss further.
Regards
David Turner
Simcyp Ltd
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The following message was posted to: PharmPK
Dear Jian,
GastroPlus(tm) was the first software to incorporate enterocyte volumes,
enzyme expressions, local permeabilities, bile salt effects, and a variety
of other considerations that are necessary for a reasonably accurate model
of absorption from the gastrointestinal tract ("All models are wrong ..." ).
Trying to build your own model to duplicate this level of sophistication is
a major effort.
We (and others like SimCYP) who have spent years doing the research,
testing, and validation of these models have incorporated them into our
commercial software. I'm sorry to say that it's a bit naive to expect those
who have made such huge investments to take you through model development
one step at a time until you've reached an equivalent model.
There are ways to gain access to GastroPlus at minimal cost if you are an
academic or government organization. Please contact us privately if you
would like to discuss using GastroPlus in your research.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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