P-glycoprotein can interact with cardiovascular drugs

P-gp drug interactions may be expected to be complex and substrate-dependent.

The majority of drug interactions today are attributed to the cytochrome P450 (CYP450) isoenzyme system. However, new data suggest that transport proteins also play a key role.

One such transporter is P-glycoprotein (P-gp), a member of the ATP-binding cassette transporters and is believed to act as a biological barrier that functions to expel toxic and foreign substances from human cells. It is an intracellular, tissue specific transport system located on the apical surface of epithelial cells of the placenta and kidney, apical surface of enterocytes, apical surface of endothelial cells in brain capillaries, and biliary canalicular membrane of hepatocytes.

Due to its anatomical location, P-gp may limit the cellular uptake of medications from the circulation to the brain and placenta and from the GI lumen into enterocytes. Alternatively, P-gp may enhance the elimination of drugs out of the hepatocytes, renal tubules, and intestinal epithelial cells into the adjacent luminal space.

Multidrug resistance

In humans, two multidrug resistant gene members of P-gp have been identified: MDR1 and MDR3. The MDR1 P-gp encoded gene is believed to function as a drug efflux transporter, while the MDR3 P-gp is involved in phospholipid transport. Most P-gp drug interactions are secondary to induction or competitive inhibition of the MDR1 gene product.

Brooke Beavers

Barbara S. Wiggins

The CYP isoenzyme system and P-gp are different in terms of the mechanisms by which they alter drug pharmacokinetics, and the ability of a drug to affect both systems is well recognized. Specifically, a large percentage of drugs that inhibit the CYP3A4 enzyme also inhibit P-gp, both of which will lead to high plasma drug concentrations, and in some cases, elevated tissue drug concentrations in tissue sactuaries (eg, the brain).

Substrates, inducers, inhibitors

A number of medications are either substrates, inducers, and/or inhibitors of P-gp and CYP3A4. Similar to the effects seen with the CYP450 systems, P-gp induction results in a decrease in systemic exposure of P-gp substrates, while inhibition will increase systemic exposure. Additionally, P-gp has several substrate binding sites and ATP-binding domains that act together as a functional unit.

Because P-gp inhibitors and inducers may interact with different sites on the P-gp transporter, a variety of clinical effects are possible. As such, P-gp drug interactions may be expected to be complex and substrate-dependent. Several medications used in the cardiovascular patients (eg, acute coronary syndromes, heart failure and cardiac transplant) act as substrates for P-gp. (These medications are listed in the table.)

Human evidence

Although a variety of P-gp interactions have been demonstrated in animal models, perhaps the most convincing human evidence involves the cardiac glycosides and other cardiac drugs. For example, the classic drug interactions with digoxin (eg, verapamil, amiodarone, quinidine, diliazem) are all now believed to be due to the ability of the latter drugs to inhibit P-gp.

For example, verapamil, when administered at a dose of 160 mg, led to a 40% increase in the plasma concentration of digoxin, whereas verapamil 240 mg increased the plasma concentration of digoxin by 60% to 80%. These data propose a dose-dependent inhibition of P-gp when verapamil and digoxin are administered concomitantly.

Several of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins have been described as inhibitors of P-gp. Specifically, lovastatin and simvastatin have been identified as potent inhibitors of P-gp transport. Although atorvastatin has been described as an inhibitor of P-gp, higher concentrations are required for maximal P-gp inhibition.

Patients receiving concomitant statin therapy with other P-gp-mediated agents should be monitored closely for adverse events. Notably, some statins, such as pravastatin, have not demonstrated P-gp activity.

Although only a few cardiovascular agents have been identified as P-gp inducers, drug interactions caused by P-gp induction may also be significant. Among these agents, P-gp induction has been demonstrated with aspirin, cyclosporine, and reserpine. Induction may occur via dose-dependent, time-dependent, and/or tissue-dependent processes.

Digoxin and rifampin

Digoxin has not only shown to succumb to P-gp inhibition, but has also been studied under conditions of P-gp induction. Some of the best evidence of P-gp induction has been demonstrated between digoxin and rifampin. Rifampin, a well-known CYP450 inducer, was administered to patients also receiving digoxin. Pharmacokinetic parameters of digoxin were monitored prior to and during the addition of rifampin. The AUC of digoxin was found to be significantly affected when digoxin was administered orally with concurrent rifampin therapy, whereas the AUC of intravenous digoxin was only slightly influenced.

The intestinal P-gp content was 3.5 times higher after receiving rifampin concurrently with digoxin. This increase in intestinal P-gp content was noted to be inversely related to the changes in the oral AUC. Thus one may conclude that P-gp-mediated induction of digoxin by rifampin occurs throughout the intestine; otherwise stated, the bioavailability of digoxin is reduced by intestinal P-gp induction caused by rifampin.

Both the induction and inhibition of P-gp substrates can be complex and clinically significant. Several cardiovascular agents have been implicated in causing such interactions. Although many of the P-gp drug-interactions are difficult to predict, one should be aware of such interactions when prescribing agents that induce or inhibit P-gp.

Absorption of drugs

More data are becoming available that suggest P-gp plays an integral role on the absorption, distribution, elimination and metabolism of various drugs. Of these, absorption appears to be the most important. Although not as extensively studied as the cytochrome p450 (CYP450) isoenzyme system, genetic polymorphisms of P-glycoprotein (P-gp) also exist. Such genetic polymorphisms may play a role in evaluating the effects of P-gp drug interactions, though research in this area is somewhat limited.

Only recently has the MDR1 gene been studied in humans, and to date 16 single nucleotide polymorphisms have been identified. Two of these polymorphisms have been associated with an inverse relationship to the plasma concentrations of digoxin, a known P-gp substrate. Because the expression of P-gp can impact drug absorption and metabolism, further research in this area is necessary and warranted in order to identify the effect of P-gp polymorphisms on drug absorption, plasma concentrations, and toxicity.

It is important to recognize when P-gp substrates are given concomitantly with P-gp inducers or inhibitors in order to prevent possible drug interactions and toxicities. Future directions may include genotyping that will allow for identification of specific polymorphisms involved in drug disposition.

Brooke Beavers, PharmD is a critical care specialty resident in the University of Virginia Health System. Barbara S. Wiggins, PharmD, BCPS (AQ Cardiology) is a pharmacy clinical specialist in cardiology in the University of Virginia Health System, and a clinical instructor in cardiology at the University of Virginia School of Medicine.

Pharmacology Consult is written by members of the Cardiology Practice and Research Network, American College of Clinical Pharmacy.