P-Glycoprotein in Clinical Cardiology

HomeCirculationVol. 99, No. 4P-Glycoprotein in Clinical Cardiology Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBP-Glycoprotein in Clinical Cardiology Ignacio Rodriguez, Darrell R. Abernethy and Raymond L. Woosley Ignacio RodriguezIgnacio Rodriguez From the Division of Clinical Pharmacology, Department of Pharmacology, Georgetown University Medical Center, Washington, DC. , Darrell R. AbernethyDarrell R. Abernethy From the Division of Clinical Pharmacology, Department of Pharmacology, Georgetown University Medical Center, Washington, DC. and Raymond L. WoosleyRaymond L. Woosley From the Division of Clinical Pharmacology, Department of Pharmacology, Georgetown University Medical Center, Washington, DC. Originally published2 Feb 1999https://doi.org/10.1161/01.CIR.99.4.472Circulation. 1999;99:472–474Ever since Juliano and Ling first described P-glycoprotein (P-gp) in 1975,1 it has become an important focus of research. P-gp is a member of the ATP-binding cassette (ABC) superfamily of proteins that is highly conserved in distantly related species (from simple eukaryotes to vertebrates).2 These similarities across species suggest that P-gp plays an important role in physiological processes in normal cells. One established function is its active transport of drugs out of the cell against a concentration gradient using ATP as an energy source, which is unusual because unlike most energy-dependent pumps, it has very little substrate specificity. Humans have 2 known P-gp encoding genes, MDR1 (class I) and MDR2 (class III), both localized in chromosome 7.3 The first has been associated with the phenomenon of multiple drug resistance (MDR),4 and the second serves to transport phospholipids into the bile.5 Cloning and sequencing of the MDR gene led to the identification of the composition and structure of P-gp,6 which consists of 2 membrane-bound domains (each with 6 transmembrane segments) and 2 nucleotide-binding domains that bind and hydrolyze ATP.4The initial and major emphasis of P-gp research was to explain the occurrence of multidrug resistance in tumors that were initially exposed to a single drug and with time developed resistance to a wide range of other unrelated drugs. Concurrent with the investigation of tumor drug resistance, there have been studies linking this MDR protein with phase I and phase II drug biotransformations,7 and others have examined the expression and function of P-gp in chloroquine-resistant Plasmodium falciparum, the causative organism of malaria.8 A new focus of interest has been the study of the role of P-gp in transport of many other drugs in addition to cancer chemotherapeutic agents. This transport mechanism may have importance for both drug toxicity and drug-drug interactions. A good example of the latter is the article by Fromm et al9 in this issue of Circulation.P-gp is a phylogenetically old system that is not restricted to tumor cells but is highly expressed in normal tissues, such as biliary canaliculi, intestinal epithelial cells, proximal tubules of the kidney, adrenal glands, natural killer lymphocytes and capillaries of the central nervous system (CNS), testes, uterus, and skin.10 Its physiological role is not completely understood, but it could protect against environmental toxins and promote excretion of steroid hormones, drugs, and electrolytes. As shown in the article by Fromm et al, this membrane transporter most likely plays an important part in drug disposition; for example, it has been suggested that normal P-gp function could influence many key steps in drug kinetics, such as reducing gastrointestinal absorption, enhancing bile and urine elimination, and preventing entry of drugs to the CNS. The function of P-gp at the molecular level has been extensively characterized; it is known to be saturable for drugs, as well as osmotically sensitive and ATP dependent.11 P-gp drug substrates represent a wide variety of compounds, most of which are hydrophobic and amphipathic and usually contain electron donor groups arranged in distinct spatial patterns (see Table). P-gp modulators (also called inhibitors or chemosensitizers) may also be substrates for the transporter; however, this is not a requirement (see Table). Mechanisms of P-gp modulation include interaction with ligand binding sites on P-gp, inhibition of ATPase, alteration of membrane fluidity, inhibition of protein kinase C (altering the phosphorylation pattern of P-gp), and regulation of MDR gene expression.411Past research has focused on decreasing multidrug resistance in oncology to improve the clinical response to chemotherapeutic agents. One attempted strategy has been coadministration of a P-gp substrate and its modulators to enhance exposure to the cytotoxic drug in MDR tumor cells. The understanding that P-gp is expressed in nontumor tissues10 and that drug distribution is markedly changed in the MDR knockout mouse12 has led to the hypothesis that modulation of P-gp transport in vivo may lead to reduced drug elimination, increased drug plasma concentration, and increased drug penetrance to tissues such as brain, fetus, and germ cells, with resulting increases in toxicity. The study by Fromm et al9 tests this hypothesis by examining the clinical interaction between 2 cardiovascular drugs, digoxin and quinidine. The increase in serum digoxin concentrations in patients who receive the combination of digoxin and quinidine has been recognized for 20 years and is the result of a reduction in both the volume of distribution and the clearance of digoxin; however, the exact mechanisms for this response have been poorly understood.13 Fromm et al report in vitro data from P-gp–expressing cells demonstrating that both drugs are P-gp substrates, and quinidine, at therapeutic concentrations (5 μmol/L), inhibits polarized transcellular transport of digoxin. Animal experiments with wild-type and mdr1a knockout mice indicate that quinidine increases the plasma and tissue concentrations of digoxin in P-gp–expressing mice but not in mdr1a −/− mice. The present report provides data to support the intriguing speculation that MDR1 expression and/or alteration of its pump function plays a role in other drug-drug interactions and in the access of selected drugs to tissue compartments. For example, MDR1 modulation could change the oral bioavailability, elimination, and CNS penetration of a wide variety of important drugs (see Table). Among these are commonly prescribed cardiovascular drugs such as calcium channel blockers, quinidine, and amiodarone, whose narrow therapeutic indexes should alert the practicing cardiologist.Of particular interest to cardiovascular scientists is the fact that P-gp structure and function resemble that of ion channels. It has been hypothesized that P-gp functions as an ion channel, or at least that it regulates ion-transport mechanisms (mainly chloride).1415 It may be relevant that many P-gp modulators are also ion channel blockers (calcium, sodium, and potassium channel blockers; see Table); however, the significance of this association is unknown at present. Such an association could be an additional factor contributing to the relevance of some drug interactions to cardiology.With the current report placed in the context of previous known drug interactions, it is becoming clear that P-gp does indeed have a role in determining drug disposition and drug effects. However, it is still not clear how this influences drug metabolic processes. P-gp may be a component in the defense mechanism against xenobiotics, and drug metabolism is clearly an important step in the detoxification and disposition of xenobiotics. To date, it is known that cytochrome P-450 isoenzymes, particularly 3A (CYP3A), and P-gp share a large number of substrates and modulators and may have complementary roles in drug absorption and disposition16; however, a direct relationship between these 2 processes has yet to be established. For example, drugs that concordantly increase P-gp and CYP3A include rifampicin and phenobarbital.1718 In addition, many drugs have the characteristics of both substrates and inhibitors of P-gp and CYP3A (eg, amiodarone, quinidine, ketoconazole, calcium channel blockers, digoxin, protease inhibitors, cyclosporine, and erythromycin).19 As understanding of these relationships develops, sources of variability in the first-pass metabolism (gut wall and liver) and pharmacokinetics of drugs may be more completely explained. The interrelationship of the regulatory mechanisms of these 2 systems is an area ripe for further investigation.Known interactions, such as for quinidine and digoxin, can serve as a model system to better understand the mechanism of this and other frequently occurring drug interactions. As with most aspects of science, a new finding raises more questions than answers; in this particular case, there are still many topics to be clarified, such as the following: The functional role of P-gp and related transporters in normal tissues (intestine, liver, kidneys, brain, and heart).The precise function of intestinal P-gp as a determinant of drug bioavailability.The clinical implications of P-gp modulation.The normal variability in expression and function of P-gp (individual differences due to polymorphisms, sex, and/or race).The physiological roles of other related transporters, such as the multidrug-associated protein (MRP) and lung resistance protein (LRP).20To date, P-gp function and its physiological and clinical roles are still under investigation, but current knowledge suggests that clinicians should be aware of the potential influence of this transport system in drug bioavailability (predominantly oral bioavailability) and drug-drug interactions. Further research will enable us to better evaluate and predict its role in drug disposition, drug-drug interactions, and adverse drug reactions.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. Table 1. Summary of P-Glycoprotein Substrates and ModulatorsP-gp SubstratesAnticancer DrugsOther Cytotoxic AgentsSteroidsMiscellaneousActinomycin DColchicineAldosteroneDigoxinDaunorubicinEmetineDexamethasoneProtease inhibitorsDoxorubicinEthidium bromideRhodamine 123EtoposideMitoxantrone99mTc-SESTAMIBIMitomycinPuromycinTriton X-100PaclitaxelTrimetrexateHalofantrine2TaxolTeniposideVinblastineVincristineP-gp ModulatorsCardiovascular DrugsCyclic PeptidesSteroidsMiscellaneousBepridil1Cyclosporine ACortisolAntibioticsDiltiazem1SDZ PSC 833ProgesteroneCefoperazoneNicardipine1ValinomycinTamoxifen2CeftriaxoneNifedipine1Tacrolimus2Erythromycin2Verapamil1ClarithromycinAmiodarone123PhenothiazinesAntimalarialsTerfenadine2Quinidine23FluphenazineMefloquineMonoclonal antibodiesPropranololTrifluoperazineQuinine23DipyridamoleQuinacrineReserpine1Calcium channel blocker;2potassium channel blocker;3sodium channel blocker.Dr Rodriguez is a recipient of a Merck International Fellowship in Clinical Pharmacology.FootnotesCorrespondence to Raymond L. 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Opie L (2000) Adverse cardiovascular drug interactions, Current Problems in Cardiology, 10.1067/mcd.2000.109090, 25:9, (621-676), Online publication date: 1-Sep-2000. Estevez M, Wolf A and Schramm U (2000) Effect of PSC 833, verapamil and amiodarone on adriamycin toxicity in cultured rat cardiomyocytes, Toxicology in Vitro, 10.1016/S0887-2333(99)00087-9, 14:1, (17-23), Online publication date: 1-Feb-2000. February 2, 1999Vol 99, Issue 4Article InformationMetrics Copyright © 1999 by American Heart Associationhttps://doi.org/10.1161/01.CIR.99.4.472 Originally publishedFebruary 2, 1999 KeywordsgenesEditorialsdrug resistanceglycoproteinspharmacokineticsPDF download Advertisement