play a large role in the distribution and elimination of many clinically
important therapeutic substances. Prescription and OTC drugs, foods
and substances made by the body may be inhibitors and/or inducers of
these transporters. Some drugs like cyclosporine are both substrates
and inhibitors of P-gp (ABCB1), other drugs like nifedipine are inhibitors
only and some drugs like digoxin are only substrates.
Since P-gps block absorption in the gut, they should be considered part
of the "first-pass effect". In fact, they can "set up"
or act as "gatekeepers" for later P450 cytochrome actions.
If one drug is a substrate of both P-gp and CYP3A4 (both found in close
proximity in the intestinal wall), and a second drug is added that is
an inhibitor of both P-gp and CYP 3A4 (e.g., ketoconazole, erythromycin,
mibefradil), then the first drug will be allowed in increased amounts.
Since CYP3A4 is inhibited, levels of unmetabolized drug will enter the
blood. The effect of P-gp blockade is to "open the gates"
so that the later actions of CYP3A4 inhibition will be increased.
Another example is loperamide and quinidine. Loperamide is an opiate
antidiarrheal that is normally kept out of the brain by the blood brain
barrier due to transport away from the brain by P-gp. When given with
quinidine which inhibits P-gp, more loperamide can enter the brain and
cause respiratory depression (Sadeque 2000).
Since ABCB1(P-gp) kinetics are "saturable", ABCB1s(P-gps)
can play a part in drug interactions only when the therapeutic concentration
of the substrate drug is low [e.g., digoxin, fexofenadine, talinolol,).
Many factors can alter ABCB1(P-gp) function and influence ABCB1(P-gp)-based
interactions. Genetic differences of ABCB1(P-gp) are known to exist,
and more than 100 variations have been identified, most of them, single
nucleotide polymorphisms (SNPs). A polymorphism at exon 26 (C3435) has
been shown to influence the level of intestinal ABCB1(P-gp) and the
concentration of digoxin: C3435TT with decreased ABCB1(P-gp) and increased
digoxin. This genotype has also been shown to be a risk factor for the
side effect of orthostatic hypotension of the ABCB1(P-gp) substrate
nortriptyline . There are racial differences of this polymorphism. Women
may have significantly lower hepatic ABCB1(P-gp) levels than men, which
may account for more efficient metabolism of certain drugs by women.
P-gp (ABCB1) has been implicated as a primary cause of multidrug-resistance
in tumors. The responsible gene- has been found to be MDR1. Many oncological
drugs are ABCB1(P-gp) substrates and are excluded from the brain at
the blood-brain barrier (BBB). In cases of primary or secondary brain
tumors, if an ABCB1(P-gp) inhibitor could be found that would block
the extrusion of the oncological drug from the BBB without causing toxicity,
the efficacy of such drugs might be improved. Several generations of
ABCB (P-gp) inhibitors have been evaluated with modest success. A recent
study of paclitaxel with elacridar [a third generation ABCB1(P-gp) inhibitor]
has shown promise. A similar targeted strategy for improving drug efficacy
could be useful for a wide range of brain disorders, from HIV and other
infections to mood disorders.
An understanding of the physiological regulation of these transporters
is key to designing strategies for the improvement of therapeutic efficacy
of drugs that are their substrates for P-gp activity (Sukhai 2000).
A list of P-gp (ABCB1) substrates, inhibitors and inducers is available here .
Hedman A, Meijer DK. The stereoisomers quinine and quinidine exhibit
a marked stereoselectivity in the inhibition of hepatobiliary transport
of cardiac glycosides.
J Hepatol. 1998 Feb;28(2):240-9.
Koren G, Woodland C, Ito S. Toxic digoxin-drug interactions: the major
role of renal P- glycoprotein.Vet Hum Toxicol. 1998 Feb;40(1):45-6.
Sadeque AJ, Wandel C, He H, Shah S, Wood AJ. Increased drug delivery
to the brain by P-glycoprotein inhibition.Clin Pharmacol Ther. 2000
Sukhai M, Piquette-Miller M.Regulation of the multidrug resistance genes
by stress signals.J Pharm Pharm Sci. 2000 May-Aug;3(2):268-80