PharmPK Discussion - Distribution of PGP and CYP 3A

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On 9 Jul 2002 at 15:07:28, "Bonate, Peter" (pbonate.at.ilexonc.com) sent the message


I have been trying to find out two things:
1.) What is the distribution of PGP and CYP 3A in the small
intestine.  Is it high PGP content in duodenum and then decreasing
towards jejunum with low CYP 3A activity in duodenum and then
increasing towards jejunum?  Or is it the other way around?

2.) Also, what is the consensus on grapefruit juice in the small
intestine?  PGP inhibitor, CYP 3A inhibitor, or both?

Thanks x2,

Pete

Peter L. Bonate, PhD
Director, Pharmacokinetics
ILEX Oncology, Inc
4545 Horizon Hill Blvd
San Antonio, TX  78229
email: pbonate.-at-.ilexonc.com

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On 11 Jul 2002 at 15:14:25, Carolien Versantvoort (Carolien.Versantvoort.-at-.rivm.nl) sent the message


Dear Peter,
Pgp content is reasobly high in the small intestine. The expression of Pgp
might increase towards the ileum and especially in the colon. As far as I
know expression of CYP3A is highest in the beginning of the small intestine
and decreases along the small intestine.
Grapefruit juice is inhibiting the intestinal CYP3A but I have seen papers
that it is enhancing but also inhibiting Pgp function (not  much of a
consensus).

Carolien

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On 18 Jul 2002 at 16:18:37, Walt Woltosz (walt.-at-.simulations-plus.com) sent the message


The following message was posted to: PharmPK Peter,

Check the excellent work done by Ken Thummel et al (Paine, Madani) at
the University of Washington for the distribution of 3A4 and 2D6 in
gut.

If you find anything good on P-gp, please share it. So far, I have
only seen qualitatively that P-gp increases aborally. Some newer
speculation counters that, but I haven't seen anything like the work
by Paine, Madani & Thummel to verify it either way - this is sorely
needed.

Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA  93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.aaa.simulations-plus.com

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On 19 Jul 2002 at 15:08:40, Chandrani Gunaratna (prema.at.bioanalytical.com) sent the message


Walt,

Check out Les Benet's work too. Les Benet of UCSF has done a lot on
P-gp. Actually his studies have shown that if P-gp is inhibited there
is less metabolism and more drug in the plasma. This is due to the
efflux of the drug from cells by P-gp and making it more available
for metabolism in the apical side. It seems that role of P-gp is more
complicated.

Chandrani Gunaratna

Chandrani Gunaratna, Ph.D.
Senior Research Scientist
Bioanalytical Systems
2701 Kent Avenue
West Lafayette, IN 47906
(765)463-4527

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