INTRODUCTION:

P-glycoprotein, the product of the MDR1 gene in humans, belongs to ABCB (MDR/TAP) super family of ATP-binding cassette (ABC) transporters and is located in the plasmamembrane of mammalian cells. It actively expels a number of amphiphilicmolecules that enter the cell by passive diffusion. Because its transport substrates are often toxic xenobiotics,P-glycoprotein fulfills a cellular detoxification function. ABCB1 is also known as multiple drug resistance-1 (MDR1) or P-gp. It is the first human ABC transporter cloned and characterized through its ability to confer a MDR phenotype to cancer cells. The ABC transporters are ubiquitousmembrane proteins that couple hydrolysis of ATP to the translocationof various substrates across cell membranes. Also the ABC transportersuper family has more than 1000 members with known sequences¹.

P-gp was originally recognized as a surface glycoprotein, which was over expressed in drug-resistant Chinese hamster ovary cell mutants. In humans, two

members of the P-gp gene family (MDR1 and MDR3) exist, whereas three members of this family (mdr1a, mdr1b0 and mdr20) are found in animals.

MDR1/P-gp extrudes a variety of drugs across the plasma membrane and is widely distributed, whereas the homologous MDR3/P-gp has a more restricted expression with highest expression in liver in the canalicular membranes of hepatocytes and is required for phosphatidylcholine secretion into bile.²

The overproduction of P-glycoprotein in some cancercells is responsible for the MDR phenotype, reducing the effectivenessof various cytotoxic drugs used in anticancer chemotherapy. Therefore, understanding P-glycoprotein functioningis of importance for controlling the bioavailability of many drugsof pharmaceutical interest and for improving anticancer chemotherapy.Also, the ability of P-glycoprotein to recognize a large numberof chemically unrelated molecules, all amphiphilic and neutralor cationic, is of great theoretical interest because it contradictsthe classical view of specific ligand-receptorinteractions.

Tissue Distribution and Cellular Localization of P-gp:

In normal human tissues it is found to be concentrated in a small number of specific sites.^2-4

1. Liver: Present on Biliary canalicular front of hepatocytes and on the apical surface of epithelial cells in small biliary ductules, responsible for the secretion of xenobiotics into thebile and urine⁵.

2. Colon/jejunum: On Apical surfaces of superficial columnar epithelial cells, prevent the uptake of toxic substrates and perhaps tofacilitate excretion across the mucosa of the gastrointestinaltract⁶.

3. BBB: Capillary endothelium and at astrocyteprocesses. Within the braincapillary endothelium, selectivelylocalized at the luminal membrane.¹ Prevent the uptake oftoxic substances into the brain⁷.

4. Trophoblasts in the placenta: P-gp protects the developing fetusagainst toxic substances⁸.

5. Pancreas: On apical surface of the epithelial cells of small ductules but not larger pancreatic ducts.

6. Kidney: On apical surface of epithelial cells of the proximal tubules.

7. Adrenal Gland: Diffusely distributed on the surface of cells in cortex and medulla.

P-gp expression on bone marrow stem cells protect themfrom toxic substances and could also be responsible for thetransport of certain growth factors and cytokines produced bystem cells⁹.

The concentration of P-gp is usually high in the plasma membrane of cancer cells, where it causes MDR by pumping lipophilic drugs out of the cell. Its expression on human tumors is most commonly detected in colon, renal, and adrenal carcinomas; rarely in lung and gastric carcinomas and certain germ cell tumors; and is undetectable in breast and endometrial carcinomas. Few sarcomas and none of the melanomas, neuroblastomas, gliomas, and pheochromo-cytomas have detectable P-gp expression.^3-4

Structure of P-Glycoprotein

Human P-gp is a 170 kDa transmembrane protein encoded by the multidrug resistance gene (MDR1), containing 27 exons spread over 100 kb located on the long arm of chromosome seven¹⁰. P-gp is composed of 1280-amino acid plasma membrane protein that has twohomologous halves separated by a linker region of about 80 aminoacids. Each half of the protein contains a hydrophobicregion with six putative transmembrane (TM) helices, followedby a cytoplasmic consensus ATP-binding/hydrolysis site¹¹.The TM regions are presumed to form the drug-translocating pathway whereas the ATP sites, through ATP hydrolysis, providethe necessary energy and driving force for transport of drugs^2,12-13.The 12 TMDs are thought to fold in a barrel-like conformation.¹⁰

There are two ATP-binding domains of P-gp, located in the cytosol side. ATP-binding domain(s) are also known as nucleotide-binding folds (NBFs). ABC pumps are mostly unidirectional.^2,13

Each of the two TM domains of P-gp consists of six long a-helical segments¹⁴.Five of the a-helices from each TM domain are related by a pseudo-twofold symmetry, whereas the sixth breaks the symmetry. The two a-helices positioned closest to the (pseudo) symmetry axis at the center of the molecule appear to be kinked. P-gp has amino-and carboxyl-terminals. Initially, it was believed that N-terminal ATP-binding domain contains all residues necessary to hydrolyze ATP without interacting with the C-terminal ATP-binding domain. But now it is believed that both the amino- and carboxyl-terminal ATP sites can hydrolyze ATP.^10,13

Each ATP-binding domain are composed of several conserved sequence motifs, the A-loop (an aromatic residue 25 amino acids upstream of the Walker A), the Walker A, the Walker B, the signature motif (LSGGQ motif, linker peptide or C motif) and the D, H and Q-loops.^2,15

Highly conserved Lys residue within the walker A motif of histadine permease is directly involved with the binding of ATP and a highly conserved Asp residue within the walker B motif serves to bind the Mg+ ion. Human P-gp requires both Mg (+)-ATP-binding and hydrolysis to function as a drug transporter. It has also been proposed that magnesium may play a role in stabilizing the ATP-binding site.¹⁵Specific amino acids are important in Walker A andWalker B motifs. Indeed, an amino acid change of the lysineand aspartate residues in the Walker A and the Walker B motif,respectively, in either NBD, resulted in a loss of the ATP hydrolysisactivity of the P-gp. Signature C motifs probably participate to accelerate ATP hydrolysis via chemical transition state interaction and is also suggested to be involved in the transduction of the energy of ATP hydrolysis to the conformational changes in the membrane-integral domains required for translocation of the substrate.²

Unlike the ATP-binding sites that are restricted to Walker A motifs of ATP-binding domains, many substrate-binding sites have been identified throughout the transmembrane (TM) domain of P-gp. The major drug-binding sites reside in or near TM6 and TM12, TM1, TM4, TM10, and TM11. Cross-linking studies have shown that TMD 6 and TMD 12 are close to each other and undergo conformational changes during the reaction cycle⁴ Fig: 2.

Fig: 2 the close proximity of TM2/TM11 and TM5/TM8 indicates that these regions between the two halves must enclose the drug-binding pocket at the cytoplasmic side of P-gp. They may form the "hinges" required for conformational changes during the transport cycle. In addition to the TM domains, intracellular loops and even ATP-binding domains have drug-binding sites¹⁶.

Mechanism of Drug Transport by P-gp^{4, 21,40} Different models have been proposed to explain the mechanism of P-gp mediated drug transport. The classical model invokes a pore-forming arrangement of the TMDs to suggest that P-gp acts as a transport protein by expelling drugs from the cytoplasm to the extracellular location. The hydrophobic vacuum cleaner model suggests that P-gp binds directly to the substrates on the plasma membrane and pumps them out of the cell by recognizing them as foreign to the membrane. Another model proposes a secondary role for P-gp in drug transport: it alters the intracellular pH or the membrane potential by functioning as a proton or chloride pump, and thus secondarily reduces the accumulation of weakly basic cationic lipophilic drugs.¹⁰

The flippase model is based on the idea that the substrate gains access to the core of the TMDs from the lipid bilayer after its interaction with the membrane, and P-gp flips the drug from the inner to the outer leaflet in an ATP hydrolysis dependent fashion. The underlying assumption is that the substrates would intercalate between the phospholipid bilayers prior to the interaction with P-gp. Given that the P-gp substrates are primarily cationic, lipophilic, planar molecules, such an interaction is expected if the molecule is to enter the cell. This model explains the existence of a broad spectrum of substrates handled by P-gp because of a two-tier recognition system. The substrate must first intercalate between the lipid bilayer appropriately, and then interact with the substrate-binding region of P-gp. This model also explains the differential handling of its substrates based on their lipophilicity: a drug with a higher lipid partition coefficient will be more easily removed from the lipid bilayer by P-gp than one with a lower lipid solubility independent of their relative concentrations in the system.^10,17Accumulating evidence points to this last model as the currently favored mechanism of P-gp action.¹⁰

Fig 4.depicts that drugs or substrates can cross into the cell membrane by simple diffusion, filtration, or by specialized transport, and the first step in drug efflux is drug recognition by P-gp followed by ATP-binding and subsequent hydrolysis. Finally, the generated energy is utilized to efflux substrate outside the cell membrane through central pore. The details of various steps are as follows.^4,15,17-20

Drugs/substrate recognition: The major drug binding sites reside in or near TM6, TM12, TM1, TM4, TM10, and TM11.Amino acids in TM1 are involved in the formation of a binding pocket that plays a role in determining the suitable substrate/drug size for P-gp, whereas Gly residues in TM2 and TM3 are important in determining substrate specificity. Hence, these transmembrane domains help in large to recognize substrates/drugs. In P-gp, the conserved Ser residue has been shownto be required for hydrolysis.^21-22

ATP-binding and subsequent hydrolysis: It is clear that ATP-binding and subsequent hydrolysis are essential for drug transport. Around 0.6-3 molecules of ATP are hydrolyzed for every molecule of the drug transported outside the cell. On the other hand, the study (Sauna and Ambudkar) suggested that two ATP molecules are hydrolyzed for the transport of every substrate molecule and demonstrated two distinct roles for ATP hydrolysis in a single turnover of the catalytic cycle of P-gp, one in the transport of substrate and the other in effecting conformational changes to reset the pump for the next catalytic cycle. Detailed kinetic measurements have determined that both nucleotide-binding domains behave symmetrically and during individual hydrolysis events, the ATP sites are recruited in a random manner. Furthermore, only one nucleotide site hydrolyzes ATP at any given time, causing (in this site) a conformational change that drastically decreases (>30-fold) the affinity of the second site for ATP-binding. Thus, the blocking of ATP-binding to the second site although the first one is in catalytic conformation. This is referred as alternate catalytic cycle of ATP hydrolysis and ADP release is the rate-limiting step in the catalytic cycle and the substrates exert their effect by modulating ADP release.

Furthermore, it is proposed that the two nucleotide-binding domains dimerize to form an integrated single entity containing two-bound ATP with just one of the two ATP being hydrolyzed per dimerization event. If one ATP-binding domain is not functional, there is no ATP hydrolysis even when ATP binds to other ATP-binding domain. However, contrary to this, one study suggested that ATP hydrolysis by either one or both NBFs is essential to drive transport of solutes. Mutations of either NBF1 or NBF2 reduce solute transport, but do not abolish it completely. Hence, common consensus still has to be made regarding ATP hydrolysis as one functional unit¹⁹

Efflux of substrate/drug through central pore: P-gp intercepts lipophilic drugs as they move through the lipid membrane and flips the drugs from inner leaflets to the outer leaflet and to extra cellular medium. P-gp undergoes conformational changes on binding of nucleotide to the intracellular nucleotide-binding domains. Signature C motifs are probably suggested to be involved in the transduction of the energy of ATP hydrolysis to produce conformational changes in the membrane-integral domains required for translocation of the substrate. The data reveal a major reorganization of the TM domains throughout the entire depth of the membrane on binding of nucleotide. On binding nucleotide, the TM domains reorganize into three compact domains that are each 2-3 nm in diameter and 5-6 nm deep. This reorganization opens the central pore along its length in a manner that could allow access of hydrophobic drugs (transport substrates) directly from the lipid bilayer to the central pore of the transporter. However, recently, it has been proposed that drug substrates first diffuse from the lipid bilayer into the drug-binding pocket through "gates" formed by TM segments at either end of the drug-binding pocket and then effluxes the substrate through the central pore of the transporter to outside the membrane.⁴Fig 5. Depicts that inhibition of P-gp transport of a drug could potentially result from either competition for drug-binding sites without interrupting the ATP hydrolysis, such as itraconazole a known P-gp inhibitor displays competitive interaction with cimetidine and displacement of morphine binding by verapamil, or it can result because of blockage of the ATP hydrolysis process, such as vandate, whereas drugs such as cyclosporine-A inhibit transport function by interfering with both substrate recognition and ATP hydrolysis. Recently, another mechanism has been proposed for inhibition of P-gp-mediated drug transport by an allosteric mechanism. Unlike competitive inhibitors, cis- (Z)-flupentixol (a thioxanthene derivative) does not interfere with substrate recognition or ATP hydrolysis; instead, it prevents substrate translocation and dissociation, as a result of allosterical changes produced in drug transporter.^4,12,17

Fig.2: The close proximity of TM2/TM11 and TM5/TM8

There are three groups of P-gp inhibitors or modulators .The first group of inhibitors are therapeutic agents. Invivo they function as a P-gp inhibitor only at concentrationshigher than those required for therapeutic activity. Therefore,these agents cannot be used as P-gp inhibitors in vivo becauseof their potential toxic effects. The second groups of P-gp modulators are analogues of the first group of modulators. They are morepotent and less toxic. For example, emopamil, gallopamil are analogues of verapamil; and PSC 833 is a non-immunosuppressivecyclosporine analogue. The third group of modulators are developedand targeted against specific MDR mechanisms.^23,17

P-glycoprotein activity is known to be inhibited not only by P-glycoprotein inhibitors but also during sepsis.²⁴

Thiolated polymers, so called thiomers, have been reported to modulate drug absorption by inhibition of intestinal P-glycoprotein (P-gp).²⁵.

A number of agents have been developed in an effort to modulate transporter activity including the potent and selective P-glycoprotein inhibitors valspodar, elacridar, zosuquidar, and tariquidar. These agents are intended to reverse multidrug resistance and/or improve oral bioavailability and CNS penetration.²⁶

Substrates of P-gp^4,27

Among the drugs, important ones are enlisted below.

Anticancer drugs: Actinomycin, cyclosporine-A, cisplatin, daunorubicin, docetaxel, doxorubicin, paclitaxel, teniposide, vinblastine, etoposide, imatinib and vincristine.

Cardiovascular drugs: Atorvastatin, lovastatin, bunitrolol, celiprolol, talinolol, diltiazem.

Antiviral drugs: amprenavir, indinavir, saquinavir, nelfinavir, and ritonavir

Antibacterial agents: erythromycin, rifampin, sparfloxacin, levofloxacin,

GIT drugs: Cimetidine, risperidone, domperidone, loperamide and ondansetron

Role of P-Glycoproteins in Glucocorticoid Function¹¹:

P-glycoprotein has been extensively described to regulate the intracellular levels of glucocorticoid hormones. p-glycoprotein is also present on the endothelial cells of the blood–brain-barrier, where it limits the access of glucocorticoids to the brain, p-glycoprotein also regulates the secretion of glucocorticoids from the adrenal gland into the blood stream, expels dexamethasone (a synthetic glucocorticoid) and cortisol (the main glucocorticoid in humans) from these cells, but not corticosterone (the main glucocorticoid in rodents). Antidepressants in vitro increase glucocorticoid receptor function by inhibiting p-glycoprotein and therefore increasing the intracellular access of glucocorticoids;. Cortisol is a substrate for this transporter¹¹.

Clinical Implications of P-gp⁴:

The membrane-bound drug efflux pump P-gp transports a wide variety of functionally and structurally diverse cytotoxic drugs out of tumor cells and thus believed to be one of the key molecules that cause multidrug resistance in cancer.

Anti-epileptic drug therapy:

Over expression of P-gp and other efflux transporters in the cerebrovascular endothelium in the region of the

epileptic focus may lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug-resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some commonly used AEDs are substrates.³³

Brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-gp, resulting into failure of therapy in psychotics³⁴. P-gp induction may enhance morphine efflux from the brain, thus reducing morphine's pharmacological activity.³⁵ rug resistance: This may also be induced by long-term treatment or high doses of prednisone as the result of P-gp (MDR-1) induction, and P-gp antagonists may improve the current therapeutic schemes for the treatment of myasthenia gravis.³⁶In addition to this, P-gp-dependent reduced intracellular accumulation of fluconazole, antileishmania drugs, anthelmintic drugs, and multidrug resistance in the protozoan parasite, such as Entameba histolytica is well documented.^37-40

Hence, targeted inhibition of P-gp may represent an important strategy by which this problem of MDR can be overcome.

Cardiotoxicity Related To P-Glycoproteins²:

Blockade of P-gp in vivo by multidrug resistance-reversingagents inevitably changes drug distribution and metabolism ofanticancer agents because of the inhibition of the normal protectivefunction of P-gp in normal tissues. As a result, plasma andtissue concentrations of drugs increase and may result in toxicity.Calciumchannel blockers such as nifedipine, flunarizine, verapamil,or other agents that reverse MDR increased intracellular concentrationsof anthracycline drugs such as doxorubicin, daunorubicin, andidarubicin in cardiomyocytes, potentiatingcardio toxicities. cyclosporin A or its analog PSC833 could increase doxorubicinand etoposide concentrations in several tissues including the heart. Cardio toxicities in patients were also observed with the concomitantadministration of verapamil and erythromycin or clarithromycin verapamil, clarithromycinand erythromycin are well known substratesof P-gp. Therefore a possible mechanism of action would be theincrease of drug concentrations in cardiac tissues producingcardio toxicities due to an inhibition of heart P-gp.Antihistamine agent ketotifenincrease accumulationof doxorubicin in cardiac tissues, probably due to a block ofP-gp.

Biological barriers to xenobiotics⁴:

Transport mechanisms for the extrusion of toxic xenobiotics and their metabolites from cellular environment are crucial for living organisms. Accumulation of these toxins may affect a number of regulatory and other functions, ultimately leading to cell death. The major physiological role of the multidrug transporters, especially P-gp, is the protection of our cells and tissues against xenobiotics.1,1-Bis(4-chlorophenyl)-2, , 2-trichloroethane (DDT) is an organochlorine pesticide. Its metabolite, 1,1-dichloro-2,2-bis( p -chlorophenyl)-ethene (p,p'-DDE), is a persistent environmental contaminant and both compounds accumulate in animals. DDT and p,p'-DDE's ability to induce MDR1 gene function as a defense against xenobiotic exposure. Similarly, MDR1/P-gp expression is severely increased by plastic-derived xenobiotics and can decrease toxicity by removing environmental toxicants such as pesticides and heavy metals from cells in mammals. P-gp modulators should, therefore, be carefully used, because some modulators that reverse P-gp efflux action in vitro may lead to alterations of tissue function and increased toxicity of xenobiotics in normal tissues

Pharmacokinetic implication of P-glycoproteins:

Absorption: P-gp efflux pump is localized in a wide range of tissues, including enterocytes of the GI tract. An increasing number of drugs, including HIV protease inhibitors such as indinavir, ritonavir, and saquinavir, and anticancer drugs such as paclitaxel, docetaxel, have been reported to be substrates for P-gp and it can significantly limit the oral bioavailability of these drugs in dose-dependent manner.^41, On the other side, P-gp substrates, such as digoxin, paclitaxel, talinolol, and saquinavir, which exhibited high efflux, showed improved bioavailability in the presence of P-gp inhibitors.⁴² Most of the P-gps are found towards the upper limits of molecular weight (>500) and calculated total polar surface area (>75 A). This indicates that unfavorable chemical features of P-gps limit passive permeability, and thus are more susceptible to P-gp-mediated efflux^.43

Quinidine increases the absorption and plasma concentrations of oral morphine, suggesting that intestinal P-gp affects the absorption, bioavailability, and hence clinical effects of oral morphine.⁴⁴Similarly, reducing effect on the saquinavir (SQV) oral bioavailability during ethanol consumption is owing to enhanced efflux of SQV at the intestine and liver, which is owing to excessive expression of P-gp caused by ethanol consumption.⁴⁵

Drug distribution: BBB and placental barrier are very important determinants of drug distribution and P-gp is an important component of these biological barriers.

Blood brain barrier: The P-gp has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. However, P-gp efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases.⁴⁶Such as, intracerebral concentrations of nortriptyline (antidepressant drug),⁴⁷risperidone and antiepileptic drugs. Thus in such situations, inhibition of P-gp is desirable. Combined use of P-gp inhibitors along with therapeutic agents could treat central nervous system diseases and result in improved clinical efficacy.¹⁰

Fig 6: P-gp is localized to the apical membrane of the endothelial cell and actively extrudes a variety of compounds out of the brain and into the capillary lumen.¹⁰

Another important function of P-gp in brain is to remove xenobiotics. The brain uptake of xenobiotics is restricted by the BBBas described earlier. P-gp in the brain capillary endothelial cells reduces the brain level of hydrophilic endogenous substrates produced either in the brain or peripheral organs, e.g., neurotransmitters, neuromodulators, metabolites of neurotransmitters, and uremic toxins. Its role in the etiology of some CNS diseases is also indicated.

Overexpression of P-gp and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, also may lead to drug resistance in epilepsy or intractable epilepsy. The brain is normally protected from these noxious blood-borne chemicals by the BBB with the help of P-gp. PD and Alzheimer's disease patients have reduced or dysfunctional P-gp function in the BBB, which may be one of the causative mechanisms for these states.^48-49

Placental barrier: It has been shown that nearly all drugs that are administered during pregnancy will enter to some degree in the circulation of the fetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. P-gps play a crucial role in 'restraining' the hypothalamic-pituitary-adrenocortical (HPA) system.⁵⁰P-gp limits the entry of various potentially toxic drugs and xenobiotics into the fetus and is thus considered a placental protective mechanism. It is expressed on the brush-border membrane (maternal side) of human placental trophoblast cells. P-gp is considered to regulate the transfer of several substances including vinblastine, vincristine and digoxin from mother to fetus, and to protect the fetus from toxic substances.⁵¹P-gp appears to be involved in drug extrusion, in early pregnancy more than at term when the fetus is more susceptible to exposure of drugs and toxins.⁵² One very contrary finding in placental drug disposition appeared that neither quinidine nor verapamil, known inhibitors of P-gp, affect the transplacental transfer of digoxin in vitro in normal human placenta. Thus, in contrast to the other tissues, they do not inhibit P-gp activity in term human placenta.⁵³

Its role in transplacental pharmacotherapy is also promising. Sustained fetal tachyarrhythmia is a potentially life-threatening condition for the unborn. Digoxin is commonly used as an initial monotherapy., it is a challenging task to maximize fetal drug exposure, whereas minimizing drug exposure of the mother. P-gp expressed in placenta decreases fetal exposure to maternal digoxin; thus, pharmacological manipulation of drug transporters may open a door to ultimate optimization of the transplacental pharmacotherapy^.
54-55

Drug metabolism: Intestinal CYP3A4-mediated biotransformation and active efflux of absorbed drug by P-gp are major determinants of bioavailability of orally administered drugs. it is a challenging task to demonstrate in vivo in humans that the functions of CYP3A4 and P-gp in enterocytes are complementary and results to directly support this concept remain elusive. However, CYP3A4 and P-gp are clearly an integral part of an intestinal defense system to protect the body against harmful xenobiotics, and drugs that are substrates of both proteins often have a low bioavailability after oral administration.⁵⁶The low oral bioavailability of the saquinavir is dramatically increased by co administration of ritonavir. Because saquinavir and ritonavir are substrates and inhibitors of both the drug transporter P-gp and of the metabolizing enzyme CYP3A4, the highly increased bioavailability of saquinavir because of ritonavir coadministration most likely results from reduced saquinavir metabolism.⁵⁷

Less potent P-gp inhibitors, such as valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as quinidine and verapamil, had modest or little effect on brain-plasma ratios but increased plasma nelfinavir concentrations owing to inhibition of CYP3A-mediated metabolism.⁵⁸

Overall, P-gp induction in vivo is tissue-specific whereas, CYP3A induction is inducer-dependent.⁵⁹A chronic treatment with rifampicin induces the expression of transport proteins and of CYP 3A4 and could therefore alter

kinetics of drugs that are their substrates.⁶⁰ Atazanavir is an inhibitor and inducer of P-gp as well as a potent inhibitor of CYP3A in vitro, suggesting a potential for atazanavir to cause drug-drug interactions in vivo.⁶¹

Drug excretion:

Renal excretion -The renal excretion of a drug can essentially be divided schematically into three functional processes: glomerular filtration, tubular reabsorption and tubular secretion. Historically, two distinct tubular secretion mechanisms have been described for drugs: one via organic cations and the other via organic anions. More recently, a third tubular secretion mechanism has been identified, mediated by P-gp.⁶²

Numerous drug interactions can result, if P-gp in renal epithelium is modulated by some drugs. Reduced nonglomerular renal clearance of digoxin contributes to the interaction between digoxin and clarithromycin, probably owing to inhibition of intestinal and renal P-gp.⁶³ Verapamil can increase the plasma concentration of digoxin up to 60-90% by Inhibition of P-gp activity in noncompetitive manner may result in a decreased renal tubular elimination of digoxin.⁶⁴

Cyclosporine-A inhibits the transepithelial transport of digoxin mediated by human P-gp and therefore reduces the renal tubular secretion of digoxin by the kidney.⁶⁵Pazufloxacin is excreted into the urine via P-gp. Cyclosporine and Sparfloxacin, a P-gp substrate significantly increases the steady-state concentration of pazufloxacin in plasma by decreasing the tubular secretion and glomerular filtration rate.⁶⁶

Biliary excretion:

Effects of various types of P-gp modulation on the biliary excretion index (BEI; a relative measure of the extent of biliary excretion) and the in vitro biliary clearance, CL (bile) suggests significant reductions of BEI and CL (bile) in the presence of the P-gp inhibitors like verapamil and progesterone. The P-gp activator quercetin enhances CL (bile) by approximately fourfold, with only a minor effect on BEI, suggesting that quercetin has a more pronounced effect on uptake at the basolateral membrane rather than excretion across the canalicular membrane. Azithromycin can modify the hepatobiliary excretion of doxorubicin-a substrate for P-gp in vivo.⁶⁷ Cyclosporine A and erythromycin have a much stronger inhibitory effect on the biliary excretion of grepafloxacin than doxorubicin⁶⁸, whereas; erythromycin competitively inhibits P-gp-mediated biliary excretion of doxorubicin.⁶⁹ All these findings suggest that P-gp plays a very important role in biliary drug excretion and various drug interactions are possible⁷⁰.

Herbal Drug Modulation:

Many herbal dugs have been suggested to produce drug interaction mediated by P-gp modulation. St. John's wort (H. perforatum) is one of the most commonly used herbal antidepressants. St. John's wort decreases the blood concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, methadone, midazolam, nevirapine, phenprocoumon, simvastatin, tacrolimus, theophylline, and warfarin. It decreases the plasma concentration of the active metabolite SN-38 in cancer patients receiving irinotecan treatment. St. John's wort did not alter the pharmacokinetics of tolbutamide, but increased the incidence of hypoglycemia. Several cases have been reported on the fact that St. John's wort decreases cyclosporine blood concentration, leading to organ rejection. St. John's wort caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also causes serotonin syndrome when coadministered with selective serotonin-reuptake inhibitors, e.g., sertaline and paroxetine. This happens because it is a potent inducer of CYP 3A4 and P-gp, although it may inhibit or induce other CYPs, depending on the dose, route, and duration of administration.^71-72

Piperine, a major component of black pepper, inhibits human P-gp and/or CYP3A4 and can affect plasma concentrations of P-gp and CYP3A4 substrates in humans.⁷³ Grapefruit juice components inhibit CYP3A4-mediated saquinavir metabolism and also modulate, to a limited extent, P-gp-mediated saquinavir transport.⁷⁴

Bitter melon affects the drug bioavailability by specifically inhibiting the efflux mediated by P-gp.⁷⁵Dietary photochemical, such as capsaicin, curcumin,⁷⁶ gingerol, and resveratrol, have inhibitory effects on P-gp and have potencies to cause drug-food interactions.⁷⁷Curcumin-I is the most effective MDR modulator among curcuminoids and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells.⁷⁸

Polymorphism of P-gp:

There are variations in P-gp expression and function among patients.These variations could contribute tothe interpatient variabilities in plasma protease inhibitorconcentrations and might be of clinicaluse. If the MDR-1 genotype in patients is known before the startof treatment with protease inhibitors, one could predict whichpatients are at risk for having low plasma protease inhibitorlevels. This could justify a dose adjustment at the start oftreatment¹⁷. So far, 28 single nucleotidepolymorphisms have been found at 27 positions⁷⁹, andthese are sometimes linked to each other. A C/T polymorphismin exon 26 (C3435T) correlates in a significant manner withP-gp expression and activity in the duodenum^17,79-80 polymorphisms may affect drug disposition, can result into variable drug effects, and can change disease risk susceptibility.⁸¹ Intracellular concentration of HIV PIs and antiretroviral efficacy is affected by variable P-gp expression, as a result of the polymorphism of MDR1 3435 C/T.⁸²Polymorphisms in MDR-1 alleles might be of clinical importancein HIV treatment, although controversy remains about the effectsof the different polymorphisms on P-gp expression and function it is not clear whether a C or a T alleleat position 3435 in exon 26 is associated with a higher levelof P-gp function. Patients with a homozygous T genotype at exon26 had, on average, a lower concentration of nelfinavir in plasmacompared with that in the plasma of patients with the homozygousC genotype⁸³. This finding suggests that the T allele isassociated with a higher level of P-gp function, this wasdifficult to reconcile with the fact that the level of P-gpmRNA transcription in PBMCs was lower in these patients. Inthat study plasma efavirenz levels were also lower in patientswith the homozygous T genotype, although efavirenz is not asubstrate for P-gp¹⁷.

Phenytoin, an anticonvulsant, exhibits nonlinear pharmacokinetics with large interindividual differences. These interindividual differences in dose response can partially be explained by known genetic polymorphisms in the metabolic enzyme CYP2C9 and part of this variability might be accounted for by variable uptake of phenytoin, which is a substrate of P-gp, encoded by the human MDR1 gene.⁸⁴, MDR1 polymorphism, via altered P-gp expression in BBB, can affect the intracellular concentrations of potentially neurotoxic substances, leading to increased susceptibility for development of Parkinson's disease.⁸⁵

CONCLUSION:

In conclusion, P-gp is an important component of BBB and placenta barrier, and functions as a protective biological barrier by extruding toxins, drugs, and xenobiotics out of the cell. It not only causes multidrug resistance in cancer but it has also been found to be responsible for MDR of many other clinically important drugs. Altered P-gp expression can lead to increased susceptibility for development of certain diseases also, such as Parkinson's disease, Alzheimer's disease, and refractory epilepsy. Hence, targeted inhibition of P-gp may represent an important strategy by which this serious clinical problem can be overcome. It is increasingly being recognized to play an important role in processes of absorption, distribution, metabolism, and excretion of many clinically important drugs in humans. Because of its importance in pharmacokinetics, P-gp transport screening has to be incorporated into the drug discovery process. Inhibition or induction of P-gp by various drugs or herbs can lead to significant drug-drug or drug-herb interactions, thereby changing the systemic or target tissue exposure of the drug. On the other hand, the magnitude of P-gp-mediated drug interactions may be underestimated because of overlapping substrate specificity between CYP-3A4 and P-gp and because of similarities between P-gp and CYP3A4 inhibitors and inducers. But it is clear that drug interaction mediated by P-gp may have a great impact on drug disposition particularly regarding brain and placenta. Thus, care evaluation is desired while indicating mechanism of drug interactions. Genetic polymorphism of P-gp has also been recorded recently, which may affect drug disposition and produce variable drug effects. As drug interactions and genetic polymorphism are important factors taken into consideration for new drug development. Thus, with such a pharmacological relevance associated with P-gp, it may have an impact on drug development in future.

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Received on 12.08.2008 Modified on 22.08.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 298-309

CAUSE	DRUGS	EFFECT
Over expression	Antineoplastic agents-vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxols.	show intrinsic resistance to chemotherapy
Induction	Antineoplastics such as cisplatin, doxorubicin, or paclitaxel	Failure of ovarian cancer therapy
Inhibition	Imatinib mesylate (potent and selective tyrosine kinase inhibitor)	Co-administration of P-gp inhibitors may improve delivery of imatinib to malignant gliomas.

Significance of P-Glycoproteins as a Transporter System

Sushant S Dhavale*, AV Bhosle, SR Hardikar and Tushar R Kotkar

Fig. 5: INHIBITION OF P-gp

CONCLUSION: