P- Glycoprotein- A Unique Transporter Pump

Manisha D. Patel¹*, Jigna S. Shah¹ and Parloop A. Bhatt²

¹Shri Sarvajanik Pharmacy College, Mehsana.

²L. M. College of Pharmacy, Ahmedabad.

ABSTRACT:

P-Glycoprotein (P-gp)/MDR1 is the 170-kDa ABC drug transporter protein. It is a member of the ABC(ATP Binding Cassette)super family.It is involved in limiting the harmful exposure of toxins, drugs, and xenobiotics to the body by extruding them into the gastrointestinal tract, bile and urine. Drugs or substrates can cross into the cell membrane by simple diffusion, filtration, or by specialized transport. 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. P-gp acts as a rate limiting step during various stages of pharmacokinetic of drug but mainly on the absorption. Different drugs have different impact on P-gp expression. Some drugs are substrate of p-gp while some are inducers or inhibitors of P-gp. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug–drug interactions with altered drug pharmacokinetics and response of drug. P-gpmayshow gender basis differences and so drug effect in individuals.

KEYWORDS:

1. INTRODUCTION:

1.1 The P-glycoprotein gene family:

The absorption of drugs from the intestine is an important factor in determining their bioavailability. There are two types of transporters: efflux and influx. Efflux transporters include P-gp. These pump out drugs from the enterocytes into the lumen, thus decreasing their oral bioavailability. Influx transporters such as Organic anion transport proteinOATP enable enterocytes to uptake drugs from the lumen increasing their oral bioavailability.¹

P-Glycoprotein (P-gp)/MDR1,the 170-kDa ABC drug transporter protein, a member of the ABC superfamily, is expressed as a result of transcription of the ABCB1/MDR1 gene.² P-gp in higher mammals forms a small gene family, with two isoforms expressed in humans, and three isoformsin rodents. The Class I and III isoforms (human MDR1/ABCB1, mouse mdr1/Abcb1a and mdr3/Abcb1) are drug transporters, while the Class II isoforms (human MDR2/3/ABCB4, mouse mdr2/Abcb4) carry out export of phosphatidylcholine (PC) into the bile.³ Its intracellular localization, the P-gp transporter can limit cellular uptake of drugs from the blood circulation into the brain and placenta, kidney and from the gastrointestinal lumen into the enterocytes.⁴

1.2 Different binding site on P-gp:

Evidence suggests that P-gp/MDR1 has multiple binding sites divided evenly into two categories: transport and regulation.^5,6 The N- and C-terminal halves of P-gp/ MDR1 contain binding sites, and these two sites may generate a single region in the overall protein structure.⁷The presence of multiple drug binding sites on P-gp/MDR1 could provide an explanation for the wide range of compounds known to interact with this protein. Previous studies have determined that there are two major substrate binding sites on P-gp/MDR1, namely at the TMD (Trans Membrane Domain) sites 5 and 6 and TMD sites 11 and 12.⁸[Figure 1.]

FIGURE 1: Structure of P-glycoprotein¹⁰

All binding sites of P-gp/MDR1 appear to be able to switch between high- and low-affinity conformations, along with modulators affecting their action from transporting sites. This might be caused by stimuli such as substrate binding and/or ATP hydrolysis.Conformational changes in P-gp/MDR1 have been demonstrated using 2H/H-exchange kinetics, proteolytic accessibility, and changes in antibody epitope recognition.⁹ There is a strong need to elucidate the molecular mechanism of substrate recognition, binding, and transport by P-gp/MDR1. This information might enable the development of novel drugs that bypass recognition by P-gp/MDR1. In addition, new drugs could be designed and generated that bind tightly to P-gp/MDR1 and inactivate it.¹⁰

1.3 ATP-binding domains:

Both NBDs (Nucleotide Binding Domain) are essential for proper functioning of P-gp/MDR1 and the activity of P-gp/MDR1 is entirely dependent on the presence of ATP.¹¹ The ATP-binding domains act as ATPase, which converts ATP to ADP to provide the energy required for P-gp/MDR1 to pump substrates across membranes, often against steep concentration gradients.¹²

2. Mechanism of action:

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.¹⁰ The details of various steps are as follows.

2.1 Drugs/substrate recognition:

The major drug binding sites reside in or near TM6, TM12, TM1, TM4, TM10, and TM11.^13,14 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.¹⁵

2.2 ATP-binding and subsequent hydrolysis:

ATP binding and hydrolysis to the conformational changes that most probably alter the drug binding affinity and/or the accessibility of drug-binding sites.¹⁶

The global changes in P-gp conformation upon ATP binding, ATP hydrolysis,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.¹⁷

2.3 Efflux of substrate/drug through central pore:

The data reveal a major reorganization of the TM domains throughout the entire depth of the membrane on binding of nucleotide.¹⁸ 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^.19

3. Effect of p-glycoprotein on pharmacokinetic:

The contribution of P-gp in limiting intestinal absorption is determined by (i) affinity of drugs towards P-gp, (ii) the passive permeability of the drug molecules across the enterocytes, (iii) expression levels of P-gp and variability in expression levels along the gut, and (iv) physiological variables that influence the solubility and passive transport along the gut.²⁰ [Figure 2.]

FIGURE 2: Drug Pumped Out from Intestinal Cells into Lumen of Gut^[1]

Intestinal P glycoprotein is well known to limit the absorptionof xenobiotics and is believed to act as a cytotoxic defense mechanism.²¹ Oral administration is the most popular route for drug administration since dosing is convenient and non-invasive and many drugs are well absorbed by the gastrointestinal tract.

There are two principal routes by which compounds may cross the intestinal epithelium: paracellular or transcellular. A number of small hydrophilic, ionised drugs are absorbed via the paracellular pathway.²² However, absorption via this route is generally low since intercellular tight junctions restrict free transepithelial movement between epithelial cells. The transcellular absorption of hydrophilic drugs may be facilitated via specific carrier-mediated pathways by means of utilizing the same route of absorption followed by nutrients andmicronutrients. Many orally administered drugs are lipophilic and undergo passive transcellular absorption.²³ Drugs that cross the apical membrane may be substrates for apical efflux transporters, which extrude compounds back into the lumen.^24,25 These apical efflux transporters are principally ABC proteins such as P-gp and MRP2, and are ideally situated to act as the first line of defense by limiting the absorption of potentially toxic ‘foreign’ compounds.²⁶

4. Impact of drugs on p-glycoprotein:

4.1 Substrate of p-gp:

P-gp/MDR1 has an important role in drug resistance and a drug’s pharmacokinetics, a number of studies have been undertaken to elucidate the molecular attributes required for interaction between this protein and its small molecule substrates.¹⁰ The most P-gp/ MDR1 substrates possess two or three electron-donor groups with a fixed spatial separation of 2.5 and 4.6A ˚, respectively, with an increased number of these elements increasing the affinity for drug binding. Correspondingly, there are a high percentage of amino acids with hydrogen bonding donor side-chains in the transmembrane sequences of P-gp/MDR1 responsible for substrate recognition.²⁷ Further studies have found that partitioning into thelipid membrane is the rate-limiting step for the interaction of a substrate with P-gp/MDR1and that dissociation of the P-gp–substrate complex is determined by the number andstrength of the hydrogen bonds formed between the substrate and P-gp/MDR1.²⁸

Other studies have suggested that there might be some physicochemical characteristic features such as lipophilicity, hydrogen-bonding ability, molecular weight, and surface areathat contribute to a drug’s binding ability to P-gp/MDR1.^29,30These compounds generally have a relatively highconcentration of electronegative groups such as oxygen, nitrogen and groups with anorbitalwithin an unsaturated system.Identification of molecular properties required for the recognition of compounds by P-gp/MDR1 as substrates is useful in rationally directing lead optimization towards the desiredP-gp/MDR1 interaction (e.g. efflux, inhibition or no interaction).³¹ Given that most anti-human immunodeficiency virus (HIV) drugs areP-gp/MDR1 substrates, modification of their chemical structures leading to less recognitionby P-gp/MDR1 as substrates will lead to improved penetration to the central nervous system(CNS) and, thus, a better antiviral profile can be achieved.¹⁰List of substrate are given in [Table 1.]

4.2 Inducers:

P-gp/MDR1 is induced not only by a number of chemical compounds, but also by physical stress, such as X-irradiation, ultraviolet light irradiation, and heat shock.²⁷ P-gp/MDR1 induction by drugs is most clinically relevant in two areas of practice: the P-gp-mediated drug–drug interactions leading to altered drug absorption and oral bioavailability and the development of MDR of cancer cells to chemotherapeutic agents.³² The extent and clinical consequence of P-gp/MDR1 induction depend on factors associated with the inducer, patient and co-administered drug. P-gp/MDR1 over-expression and consequent MDR causes a major problem in cancer chemotherapy.³³ List of inducers are given in [Table 1.]

4.3 Inhibitor:

The potential therapeutic uses of these P-gp/MDR1 inhibitors is that co-administration with existing chemotherapy drugs (providing co-administration does not cause other interactions) will help to negate cancer cell MDR caused by P-gp/MDR1.³⁴ Most P-gp/MDR1 binding inhibitors share some common chemical features, such as aromatic ring structures, a tertiary or secondary amino group and high lipophilicity³⁰ although P-gp/MDR1 substrates as a whole have varying classes of inhibitory action. Some P-gp/MDR1 inhibitors are also referred to as chemosensitzers due to their ability to reduce chemotherapy drug resistance.³⁵ The main ways in which an inhibitor of P-gp/MDR1 can exert its activity are either by being a very high-affinity substrate for P-gp/MDR1 and binding non-competitively (thus not allowing other drugs to bind), or by being efficient inhibitors of ATP hydrolysis either at the ATP binding site or by inhibiting protein kinase C which is involved with ATP coupling to P-gp/MDR1.³⁶List of inhibitors are given in [Table 1.]

Table 1: List of Substrate, Inhibitors and Inducers of P-gp^[10]

Substrate	Inhibitor	Inducers
Actinomycin Daunorubicin Digoxin Diltiazem Domperidone Indonavir Irinotecan Ketoconalzole Losartan Phynobarbital Phenytoin Rifampin Ritonavir Tetracycline Topotecan Quinidine Vincristine Verapamil	Amiodarone Astemizole Atorvastatin Bromocriptine Carvedilol Cyclosporine Diltiazem Dipyridamole Disulfiram Erythromycine Fluoxetine Itraconazole Progesterone Quinidine Reserpine Terfinadine	Amiodarone Colchicine Diltiazem Insulin Methotrexate Midazolam Morphine Nelfinavir Nifedipin Phenothiazine Phenytoin Probenacid Reserpine Rifampicin Ritonavir St John’s wort Verapamil Yohimbine

5. Gender and Age Related Differences in P-Glycoprotein Expression:

Some authors suggest thatactivity is one-third to one-half lower in livers obtainedfrom females compared with males,³⁷ however inother in vitro study there were no difference in the expressionof P-gp.³⁸ It is not easy to establish the role ofP-gp in the gender-related differences in the oral pharmacokineticsof drugs for the above mentioned that CYP3A4and P-gp share substrates.^39,40Since several factors may contribute to gender differencesin the absorption of drugs, the final result will dependon the characteristics of the compound and the extentof gender differences of each of the factors described.⁴¹

P-glycoprotein and CYP3A4 act in concert to reduce absorption of xenobiotics along the gastrointestinal tractand increase drug elimination from the liver.In addition, p-glycoprotein increases fecal elimination by extruding drug into bile.⁴²Genetic deficiencies in p-glycoprotein reduce drug excretion into bile and increase drug half-life of p-glycoprotein–dependent drugs.⁴³Intracellular levels of p-glycoprotein substrate drugs are increased when p-glycoprotein is blocked or geneticallyreduced^42,44-46Reduced p-glycoprotein predisposes to greater competitive intracellular drug interactionsfor CYP3A4.⁴⁴ CYP3A4 in humans is generally the same in females and males, but hepatic p-glycoprotein is 2.4-fold lower in females.^44,47Reduction inp-glycoprotein in females relative to males will reduceelimination and prolong drug half-life. Reduction in glycoprotein will lead to accumulate of these glycoproteinsubstrate drugs in brain, heart, liver, and gastrointestinal tract.^45,46,48,49The end result is a greater risk for myelosuppression and gastrointestinal toxicity in females and prolonged drug elimination.⁵⁰ In summary, sex differences in p-glycoprotein will influence intracellular levels of p-glycoprotein substrate drugs; increase competitive drug interactions and delay drug elimination.⁵¹ As a result; females will experience greater drug toxicity with p-glycoprotein substrate drugs.⁵² Females have been shown to be a risk factor for clinically relevant adverse drug reactions with a 1.5 to 1.7-fold greater risk of developing an adverse drug reaction compared to male patients.⁵³

The effect of age on P-Glycoprotein expression and functionin the Fischer-344 ratwasexamined in five different tissues. An age-related increase inP-gp expression was evident in the liver and lymphocytes,whereas a reduction was observed in the kidney. In intestinalcells and endothelial cells of the BBB, there was no apparentchange with age. Of all tissues examined, P-gp expression inthe intestine and the BBB displayed the greatest variability.⁵⁴The digoxin pharmacokinetics were investigated in the elderly healthy subjects and compared with those of the younger patients. It showed no statistically significant differences in comparison with the younger age group. Even statistical differences in the digoxin pharmacokinetics between young healthy women were not seen.⁵⁵Some study in humans suggests that cerebral P-gp function decreases with age and it may cause neurodegenerative disease.⁵⁶

6. CONCLUSION:

Literature studies clearly indicate the importance of understanding P-gp/MDR1 in depth. P-gp forms a functional barrier whichrestrictsaccess of various pharmacologic agents, xenobiotic excretion and cause cancer cell resistance, a thorough understanding of its mechanisms, structure, andfunction can lead to a greater understanding of drug therapy in a number of differentareas due to the great number of known substrates, inducers, and inhibitors. Currently inthe area of pharmacy practice, knowledge of P-gp/MDR1 and its potential to impactdrug dosing regimens is greatly under-appreciated. The ability of transport proteins including P-gp/MDR1, BCRP, and MRPs to reduce oral bioavailability and alter tissue distribution has obvious implications for drug design. Gender and age basis differences are also seen in the expression of P-gp.Several factors may contribute to gender differencesin the absorption of drugs with P-gp. But females are more prone to adverse drug reaction than males. Age related differences are seen in expression of p-gp is differ in different tissues.

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Received on 17.06.2011

Accepted on 29.06.2011

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Research J. Pharmacology and Pharmacodynamics. 3(5): Sept –Oct. 2011, 241-245