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The following message was posted to: PharmPK
Dear all,
We would like to study the clinical drug interactions
with Pgp inhibitor and inducer.
I would like to have suggestions on the drugs which
can be used as Pgp modulators in human beings.
I understand that Rifampicin and ketoconazole are two
drugs that have been shown to have some effect on Pgp.
However, these two drugs show overlapping profile due
to their CYT P450s.
Can these drugs be used as Pgp modulators clinically?
I would really appreciate suggestions and comments.
Sincerely
Mita
Karolinska Institute
Stockholm
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The following message was posted to: PharmPK
Dear Mita,
Regarding specific PGP modulators (inducers and inhibitors of PGP),
many of them are also substrates of CYP3A. Of the example substrates
you mentioned (ketoconazole, rifampicin), although they modulate PGP,
they are also CYP3A modulators. I am not aware of any selective PGP
inducers and/or inhibitors in vivo.
There are several papers that have discussed selective PGP substrates
[fexofenadine, digoxin] (Schwab M et al. Annu Rev Pharmacol Toxicol
2003). These have been used in human studies as "probes" of PGP.
PGP inducers that have also been used in healthy volunteer studies
include St. John's wort (Wang Z, et al. Clin Pharmacol Ther 2002) and
rifampin (Hamman M et al. Clin Pharmacol Ther 2001).
Regarding inhibitors of PGP, in addition to ketoconazole, quinidine has
been suggested. This was primarily based on a study with quinidine and
digoxin (Fromm M et al. Circulation 1999).
Hope this helps.
joema
Joseph Ma, PharmD
Clinical Pharmacology Fellow
Bassett Healthcare
1 Atwell Road
Cooperstown, NY 13326
(607) 547-3399
joseph.ma.at.bassett.org
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Dear Mita
Karolinska Institute
I wish to add comments regarding role of Pgp modulators in drug-drug
interactions.
For absorption, a clear role has emerged for P-glycoprotein in limiting
permeability across the gastrointestinal tract. As a result, a wide
variety of drugs suffer from incomplete, variable and non-linear
absorption. Similarly, at the blood-brain barrier a range of drugs has
limited brain penetration due to P-glycoprotein-mediated efflux, which
can limit therapeutic effectiveness of CNS agents. In the liver,
transport proteins are present on the sinusoidal membrane that can be
the rate-limiting step in hepatic clearance for some drugs. Mechanistic
studies clearly suggest a key role and broad substrate specificity for
the OATP family of sinusoidal transporters. Mainly ATP-dependent
transport proteins such as P-glycoprotein and MRP2 govern active
biliary excretion. Drug-drug interactions have been demonstrated
involving inhibition or induction of transport proteins. Clinically
significant interactions in the gastrointestinal tract and kidney have
been observed with inhibitors such as ketoconazole, erythromycin,
verapamil, quinidine, probenecid and cimetidine. Clinically significant
inhibition at the blood-brain barrier is more difficult to demonstrate,
relying on pharmacodynamic and toxicodynamic changes, but an example is
quinidine increasing loperamide-induced central effects in humans.
Like cytochrome P450 enzymes, inhibition and induction of P-gp have
been reported as the causes of drug-drug interactions. Because many
prototypic inhibitors and inducers affect both CYP3A4 and P-gp, many
drug interactions caused by these inhibitors and inducers involve these
two systems. Clinically, it is very difficult to quantitatively
differentiate P-gp-mediated drug interactions versus CYP3A4-mediated
drug interactions, unless their relative contributions can be
accurately estimated. Therefore, care should be exercised when
interpreting drug interaction data and exploring the underlying
mechanisms of drug interactions.
For your information I am mentioning some references:
1)Role of transport proteins in drug absorption, distribution and
excretion.Ayrton A, Morgan P.Mechanism and Extrapolation Technologies,
DMPK, GlaxoSmithKline, Welwyn, UK.Xenobiotica. 2001
Aug-Sep;31(8-9):469-97
2)Drug-drug interaction mediated by inhibition and induction of
P-glycoprotein.Lin JH.Department of Drug Metabolism, Merck Research
Laboratories, WP75A-203, West Point, PA 19486, USA.Adv Drug Deliv Rev.
2003 Jan 21;55(1):53-81.
Thanks and Regards
Dr. Sajjad A. Desai
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