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The following message was posted to: PharmPK
Dear friends,
Association of p glycoprotein and CYP3A4 is well known, which has major
impact on drug bioavailability and pharmacokinetics.
As we know, a drug can be substrate of P glycoprotein alone, CYP3A4
alone or
can be substrate of both.
I would like to know about the examples of drugs which are substrate
of P
glycoprotein alone.
Prashant
BITS, Pilani
Kole Prashant
Pharmacy Group,
Birla Institute of Technology and Science, Pilani.
Rajasthan, 333031
India
Phone: 01596-245074- ext - 458 [0ff]
01596-242824 [Res.]
Alt. Email: plkole.-a-.yahoo.com, prashantkole.at.gmail.com
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Dear Prashant,
Talinonlol, a new beta blocker, which is not on the market yet (as
much as I know), is a typical example of a P-gp substrate. It is not
a substrate of CYPs and is not metabolized by CYPs in the enterocytes.
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The following message was posted to: PharmPK
Dear Prashant,
I think digoxin might do pretty well. Good Pgp and not a cyp3a4
substrate as
far as I know
Regards
Hans Smit
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The following message was posted to: PharmPK
Dear Prashant,
There are drugs that are P-gp substrates but not CYP3A
substrates. Digoxin, as has already been mentioned, is a classic example
and fexofenadine is another example which we tend to use as a model drug
in our lab. Be careful with the word 'exclusive' though. P-gp substrates
(whether CYP3A substrates or not) are invariably substrates of other
transport proteins - particularly some of the OATPs.
Andrew
Dr Andrew Davey
Senior Lecturer
Sansom Institute
School of Pharmacy and Medical Sciences
University of South Australia.
GPO Box 2471
Adelaide SA 5001
Tel: (0) 8 8302 1127
Fax: (0) 8 8302 1087
email: andrew.davey.aaa.unisa.edu.au
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The following message was posted to: PharmPK
Dear Prashant,
Actually, the association of P-gp and CYP 3A4 is not so "well known". (I
have assumed here that you were referring to the supposed cooperation
of 3A4
and P-gp in reducing systemic availability.)
Although the cooperation of the two has been theorized, there are
many who
challenge this cooperation. There are several factors which argue
against
such cooperation:
(1) Michaelis-Menten kinetics argues that metabolism is a function of
concentration, so that anything that reduces concentration in the
cytoplasm
would reduce the instantaneous rate of metabolism. The theory says
that P-gp
efflux causes the drug to recycle and be absorbed again, providing
another
opportunity for 3A4 to metabolism it. So the lower instantaneous rate is
offset by the integrated effect over time of more exposure to 3A4.
(2) However, the expression of 3A4 is highest in proximal small
intestine,
decreasing rapidly into jejunum, ileum, and colon.
(3) And the expression of P-gp is minimal in proximal small intestine,
increasing gradually into ileum and colon. If they are supposed to
cooperate, why are their expressions the opposite? High efflux in the
colon
is more likely to lead to loss of drug due to excretion. High efflux
in the
proximal small intestine would provide the greatest opportunity for
reabsorption. So both expressions should be reversed for maximal
cooperation
(high P-gp expression in proximal regions and high 3A4 in distal
regions).
(4) A few years ago when Dr. Leslie Benet began presenting this
theory, Dr.
Christopher Lipinski told an audience at a meeting I attended that he
had
done a search of the Pfizer database to identify all 3A4 and P-gp
substrates. If my memory serves me correctly, he found about 4,000
compounds
that were identified as substrates for one or the other, or both.
Again, if
my memory serves me correctly, he said there was not only no
correlation,
but it could be argued that there was an anti-correlation (more drugs
with
only one or the other, but not both).
Regarding P-gp alone - I'm not sure why some in the industry worry so
much
about it. In our experience, it's rare to find a drug that undergoes a
significant reduction in bioavailability as a result of P-gp. For most
compounds (not all of course) it appears to be easily saturated at
clinical
concentrations. Drugs with adequate permeability and solubility will be
substantially absorbed in the proximal small intestine, where P-gp
expression is lowest (which would make them more susceptible to 3A4
metabolism, like midazolam).
Others have already noted that it may be difficult to find drugs that
are
substrates of P-gp alone.
I hope this helps.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
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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