P-glycoprotein: why is it significant?
P-glycoprotein is the most well known member of a family of transmembrane proteins called the ATP-binding cassette family (ABC). These proteins bind ATP and use this energy to transport substances across cell membranes.
The naming of ABC transporter proteins follows similar conventions to the naming of the cytochrome P450 isoenzymes so P-glycoprotein, which is part of ABC subfamily B, is also known as ABCB1.
P-glycoprotein transports substances out of cells and is classified as an efflux pump. It was the first human ABC transporter cloned, and was initially of interest because it gave cancer cells a form of multidrug resistance by transporting some types of chemotherapeutic agent (eg, paclitaxel) out of the cells at which they were targeted. (Hence P-glycoprotein is sometimes also referred to as MDR1.)
As well as being present in tumour cells, P-glycoprotein is widely distributed and is thought to function as a protective barrier by actively limiting the absorption and distribution of substances (including drugs) and altering the extent of elimination. As a result, P-glycoprotein can be found in:
• Cells lining the intestine (where it affects the absorption of oral drugs by ejecting molecules of drug that have already been absorbed back into the gut lumen)
• Cells at the blood-brain barrier (where it can reduce central nervous system adverse effects or limit a drug’s efficacy by ejecting it from the brain)
• Liver and kidney cells (where it affects the elimination of drugs)
P-glycoprotein in drug interactions
P-glycoprotein might be affected by drugs in a similar manner to cytochrome P450 isoenzymes, that is, it might be inhibited (reducing its efflux effects) or induced (resulting in an increase in P-glycoprotein levels, and therefore increased efflux effects).
• P-glycoprotein (ABCB1, MDR1) is found in the intestines, liver, kidneys and blood-brain barrier. It is thought to serve a protective function, transporting substances (including drugs) out of cells.
• Like cytochrome P450, P-glycoprotein can be inhibited or induced.
• P-glycoprotein has been implicated in interactions, for example, between verapamil and digoxin.
• There appears to be a link between P-glycoprotein and CYP3A4 — some drugs are substrates of both.
• More research is needed for the clinical significance of P-glycoprotein interactions to be appreciated.
The outcome of this inhibition or induction depends on the location of the affected P-glycoprotein. For example, loperamide is thought to lack adverse effects in the central nervous system because it is removed from the brain by P-glycoprotein. However, in the presence of the anti-arrhythmic quinidine, which inhibits this efflux, some patients can develop central nervous system adverse effects as a result of the increased exposure to loperamide.
Another example of P-glycoprotein inhibition relevant to drug interactions is the effect of verapamil on the P-glycoprotein-mediated renal and biliary clearance of digoxin. This results in an overall reduction in digoxin excretion and an increase in its blood levels. In most cases, this means that a reduction in the dose of digoxin is likely to be needed to prevent toxicity.
However, not all P-glycoprotein drug interactions with digoxin result in clinically relevant effects. For example, rifampicin induces P-glycoprotein in the intestine, leading to a reduction in digoxin absorption, but the decrease in digoxin levels is modest and not all patients will be affected to a clinically significant extent.
Investigating drug interactions
Mechanisms of drug interactions can be examined using substances (probe substrates) that are specific to a particular metabolic pathway or route of elimination.
Digoxin and the beta-blocker talinolol are considered by most as suitable probe substrates for P-glycoprotein because they are not metabolised so are more specific for it. However, both are now thought to be substrates for other transporters and some researchers are questioning their P-glycoprotein specificity. Nevertheless, examining the behaviour of digoxin is currently one of the best ways to assess the effects of other drugs on P-glycoprotein.
Interplay with CYP3A4
Many drugs that are substrates of P-glycoprotein are also substrates of CYP3A4. There is evidence that these two systems work in a co-ordinated manner and the interplay between them will, therefore, affect the overall outcome of any interaction.
There is also a similar overlap of inhibitors and inducers between the two systems. For a dual substrate, the concurrent use of a drug that inhibits both intestinal P-glycoprotein and intestinal CYP3A4 will decrease the amount of drug pushed out of the cells lining the intestinal lumen by P-glycoprotein and decrease the metabolism by CYP3A4, thus increasing the bioavailability of the drug.
This interplay might be involved in many of the drug interactions traditionally thought to be due to changes in CYP3A4 activity and might help to explain differences in the effects of drugs previously thought to affect CYP3A4 to similar extents. For example, both verapamil and diltiazem are considered to be moderate inhibitors of CYP3A4, but the change in the AUC (area under the curve) of sirolimus seen with verapamil is considerably greater than that seen with diltiazem. Verapamil is a well known P-glycoprotein inhibitor, whereas diltiazem is not known to affect P-glycoprotein and it might be the dual inhibitory effect of verapamil on both CYP3A4 and P-glycoprotein that results in the greater effect on sirolimus levels.
The exact nature of the interplay between the two systems and its involvement in drug interactions is complex and the subject of ongoing research. The net effect of interactions involving both systems may ultimately depend on the relative affinities of a drug for P-glycoprotein and CYP3A4 and the magnitude of the inhibition or induction on these systems.
There are still many other questions surrounding P-glycoprotein and its influence on drug interactions, including:
• Does separating the doses of drugs reduce the effect of P-glycoprotein on absorption?
• How quickly is P-glycoprotein affected by inhibitors or inducers?
• Does inhibition or induction occur with single doses of drugs?
• How long does the interaction last after the inhibitor or inducer is stopped?
There appears, as yet, to be no firm evidence to confirm the answers to these questions but as more research is published, the overall clinical significance of
P-glycoprotein to drug interactions will be better understood.
However, because P-glycoprotein is now often mentioned in product literature from manufacturers, it is important that pharmacists develop an awareness of this transporter and an understanding of its effects and relevance to drug interactions.
This article has been produced by Julia Sawyer, Jennifer Sharp and Karen Baxter, on behalf of the Stockley editorial team.
Citation: The Pharmaceutical Journal URI: 11076309
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