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Novel Drug Delivery Approaches to bypass P- Glycoprotein Efflux Pump

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Key Words: MDR1, ABCB1, P-gp efflux pump, P-gp substrates, P-gp inhibitors, MRP

1. Abstract:-

P-glycoprotein (P-gp, Permeability glycoprotein) is a very well investigated efflux pump of the Multi Drug Resistant genes (MDR) subfamily. P-gp is energy dependent transporter protein involved in effluxing a number of drugs and impedes their absorption
intracellularly. Multi Drug Resistance (MDR) of tumor cells is the main cause of the failure of chemotherapy. Tumor cells carrying MDR phenotype are often associated with over expression of some of these drug efflux pumps, called as (P-gp) P-glycoprotein efflux pump. P-gp is highly expressed over Blood Brain Barrier due to that P-gp inhibits the entry of various drugs that are used for the treatment of various CNS disorders and chemotherapy, such as cerebral human immunodeficiency virus (HIV) infection and brain tumors. P-gp is also present over the gastrointestinal tract, which impedes pharmacokinetic parameter of many drugs and ultimately affects bioavailability and failure of therapy by peroral route.

This review focuses on the various strategies such as by the use of P-gp modulators (reversal agents). Other approach is by controlling the expression of the P-gp proteins by various strategies, also by use of colloidal drug carriers like Liposomes and Nanoparticles combined with API with P-gp modulator that can be used to overcome P-gp efflux pump activity that are discussed in detail.

2. Introduction:-

P-gp is determined by MDR1 in humans. [1,2] P-gp can efflux out a variety of drugs from cells [3], which ultimately lead to unsuccessful drug therapy. It also affects various pharmacokinetic parameters of drugs those are P-gp
substrates like absorption, distribution, metabolism and excretion from the body which leads to modified bioavailability and possible adverse drug
reactions.[4]

Knowledge of the approaches to circumvent P-gp efflux pump is critical for targeted drug therapy and formulation design and development of dosage forms. It is established that drugs and excipients interact with P-gp is a complicated procedure and information of its mechanism of interaction are still unclear.[5,6] This review endirects the formulation aspects of potent therapeutic agents in the direction of dose reduction with better bioavailability by exact selection of excipients and providing synergism by selecting suitable therapeutic agent. Many attempts have been made to bypass P-gp efflux pump by means of novel drug delivery approaches.

3. P-gp Structure And Its Tissue Distribution:-

3.1 Structure:

P-gp is composed of polypeptide approximately 170 KDa molecular weight having 1280 long amino acid glycoprotein and comprising of two analogous fractions of same length in one line, both comprising of six trans-membrane domains and with a flexible linker polypeptide region separates two ATP binding regions.[7,8]

Structure of P-glycoprotein Efflux Pump

Figure 1: Structure of P-glycoprotein Efflux Pump.[7,8]

3.2 Tissue distribution: [9]

P-gp is widely distributed in:

Ø Intestinal Epithelium

Ø Hepatocytes

Ø Renal Proximal Tubular Cells

Ø Adrenal Gland

Ø Capillary Endothelial Cells comprising
the Blood- Testis and Blood- Brain Barrier

4. The Role Of P-gp:-

Ø P-gp preferentially effluxes hydrophobic neutral compounds from the inside of the cell back to the extracellular space.

Ø In the intestine and in the liver, P-gp increases exposure of drug to CYP enzymes. Because of this, there is increase in drug metabolism and
decrease in bioavailability.

Ø In tumor cells, P-gp transports drugs out of the cells and contributes to the multidrug resistance phenomenon (MDR).

Various models showing P-gp drug efflux mechanisms

Figure 2: Various models showing P-gp drug efflux mechanisms .
[10,11,12,13]

Where ® Drug, (1) Outer region of plasma membrane, (2) Inner region of plasma membrane, (3) Cytosolic region, (4) Protein channel

(a) Hydrophobic vacuum cleaner model,

(b) Flippase model and (c) Pore model.

The hydrophobic vacuum cleaner model merges both the features of below mentioned two models. In flippase model, drugs entrapped in the inner region of the plasma membrane, that attaches to P-gp and are effluxed to the outer region of the bilayer. In pore model, drug is connected with P-gp in the cytosol and is effluxed out of the cell via central pore channel. [10,11,12,13]

5.P-gp Substrates And Inhibitors:-

The range of substrates for P-gp is very large but includes a number of relatively large molecular weight drugs i.e. larger than 500 Da. List of P-gp substrates is shown in Table-1.

P-gp Substrates:

Ø Substrates are the compounds i.e. drugs and excipients that are effluxed out from the cell by various mechanism due to their inherent structural characteristics under the influence of P-gp efflux pump.

Chemistry of Substrates:

  • Class I elements which is having two electron releasing groups-[2.5 °A], whilst Class II elements have three electron releasing group-[4.6 °A].
  • Electron releasing group are those who have lone pair of electrons on electron withdrawing atoms or those have unsaturated system containing Π electron cloud.
  • Substrates for P-gp depend on number and strength of proton acceptor group.
  • Compounds that having at least one of the above mentioned group may act as P-gp substrates.

Ø The affinity of the substrate for P-gp depends

Simplified efflux mechanism of P-gp substrate

Figure 3: Simplified efflux mechanism of P-gp substrate. [14]

The P-gp molecule expressed over whole cell membrane so thereby it exhibit its efflux action in both inside and outside
of the cell. The middle part of the P-gp structure is a channel or pore through which drugs are effluxed out to extracellular region as shown in Figure
3. Efflux action of P-gp is energy dependent i.e. ATP mediated. [14]

Table -1 List of P-gp substrates [15]

Analgesics

Asimadoline, Morphine, Pentazocine, Methadone, Fentanyl

Antibiotics

Valinomycin, Gramicidin D, Rifampicin, Grepafloxacin, Tetracycline, Levofloxacin

Anticancer drugs


Anthracenes:

Mitoxanthrone, Bisanthrene


Anthracyclines:

Idarubicin, Daunorubicin, Epirubicin


Epipodophyllotoxins:

Teniposide, Etoposide


Taxanes:

Docetaxel and Paclitaxel


Vinca Alkaloids:

Vinorelbine, Vincristine and Vindesine


Others:

Mitomycin C, Dactinomycin, Topotecan,

Irinotecan, Tamoxifen, Methotrexate,

Trimetrexate, Amsacrine, Imitinib

Antidepressants

Venlafaxine

Antidiarrheal agents

Loperamide

Antiemetics

Ondansetron, Domperidone

Antiepileptics

Felbamate, Phenobarbital, Phenytoin, Lamotrigine, Carbamazepine

Antifungal agents

Itraconazole

Anti-gout agents

Colchicine

Beta blocker

Talinolol, Bunitrolol, Carvediol, Celiprolol

Cardiac glycosides

Digoxin, Digitoxin

Steroids

Dexamethasone, Hydrocortisone, Corticosterone, Triamcinolone, Aldosterone, Methylprednisolone

Curare

Vecuronium

Diagnostic dyes

Rhodamine 123, Hoechst 33342

HIV protease inhibitors

Saquinavir, Nelfinavir, Indinavir, Lopinavir, Amprenavir

H1-receptor antagonists

Fexofenadine, Terfenadine

H2-receptor antagonists

Cimetidine, Ranitidine

Immunosuppressive agents

Tacrolimus, Sirolimus

Statin

Lovastatin

Pesticides, Anthelmintics,

Acaricides

Ivermectin, Abamectin

P-gp Inhibitors:

Ø Inhibitors are the compounds i.e. drugs and excipients that inhibit the efflux action of P-gp.

Table -2 List of P-gp Inhibitors [1]

Antiarrythmic agents

Amiodarone, Quinidine, Verapamil

Antibiotics

Clarithromycin, Erythromycin

Anticancer drugs

Actinomycine D, Doxorubicin, Vinblastine

Antidepressants

Paroxetine, Sertraline, Desmethylsertraline

Calcium channel blockers

Verapamil, Nifedipine, Azidopine, Dexniguldipine

Calmodulin antagonists

Trifluoperazine, Chlorpromazine, Trans-Flupenthixol

Cyclic peptides

Cyclosporin A, Valinomycin

Amphiphiles and Detergents

Polysorbates, Polyoxyl 35 castor oil, Macrogol 15 Hydroxystearate

Miscellaneous

Chloroquine, Reserpine, Dipyridamole, Ketoconazole, Colchicines, Fenofibrate, Propafenone, Ritonavir

Proton pump inhibitors

Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole

Steroids

Progesterone, Tamoxifen, Cortisol

6.Novel Approaches To Bypass P-gp Efflux Pump:-

6.1 Reversal agents

6.2 Natural and Synthetic Polymers

6.2.1 Natural polymers

6.2.2 Synthetic polymers

6.3 Nanocarrier drug delivery system

6.3.1 Liposomes

6.3.2 Stealth liposomal carriers

6.3.3 Niosomes

6.3.4 Polymeric nanoparticles

6.3.5 Dendrimers

6.4 Polymeric drug conjugates

6.1 Reversal agents:

They are also called as chemosensitizers as they inhibit P-gp efflux of drugs and increase the absorption of drugs intracellularly so these agents may
be co-administered with our therapeutic agent as competitive inhibitors. [16]

Reversal agents for P-gp as per the generation:

A) First-generation agents

These agents had their own pharmacological action. These agents were used in high dose as they were not
selective to inhibit P-gp so they resulted into high toxicity which impedes their use to inhibit P-gp.


[1,17,18,19,20]

  • Cyclosporine (hepatic, renal, myeloid and neurotoxicity)
  • Verapamil (cardiotoxicity)

B) Second-generation agents

These agents were selective and less toxic than the first generation agents. Many chemotherapeutic agents are substrate
of P-gp and CYP 3A4. Same way, second generation agents were also substrate of the CYP 3A4. So these may lead to unpredictable absorption and
metabolism and these ultimately resulted into modified bioavaibility. [17,20,21]

  • Valspodar (R-enantiomer of Verapamil )
  • Biricodar

C) Third-generation agents

These agents were not the substrates of CYP 3A4 so used to overcome drawback of second generation agents and these agents
selectively and potentially inhibit P-gp.

  • Tariquidar XR9576
  • Zosuquidar LY335979
  • Laniquidar R101933

6.2 Natural and Synthetic Polymers:

6.2.1
Natural polymers
[22,23,24]

They are obtained from natural source. For example:

Ø Anionic gums:

  • Xanthan gum (Xanthomonas campestris bacterium):P-gp inhibitor at 0.05%
  • Gellan gum (Sphingomonas elodea):P-gp inhibitors at 0.05%
  • Dextran Xanthan gum (Xanthomonas campestris bacterium):P-gp inhibitor at 0.05%
  • Alginates:

i. Flavicam (Lessonia flavicams)

ii. Ascophyllum (Ascophyllum nodosum): P-gp inhibitor at 0.5 mg/ml

Ø From Green tea- Polyphenols

Ø From Grapefruit Juice- Various Polysaccharides like L-gulosyluric acid, D-mannosyluronic acid, D-glucose and/or D-glucuronic acid as well as
D-mannose, D-mannuronic acid and/or D-mannose monomers.

6.2.2 Synthetic polymers

Synthetic polymers can be synthesized by monomer polymerization or by natural polymers modifications or by combination of
natural substances with synthetic substances. e.g.: Detergents based on Polyethylene glycol, Poloxamers copolymers, Dendrimers and Thiomers.

Ø Polyethylene Glycol:

  • It has shown that PEG 400 at the concentration of 1-20% significantly increases Digoxin intracellular accumulation due to inhibition of P-gp
    activity. PEG-2000 and PEG-20000 also been tested for P-gp inhibition by various researcher. [25,26,27]
  • PEG 300 (20% v/v) has shown almost complete and Cremophor EL (0.1%w/v) and Tween 80 (0.05% w/v) has shown only partial inhibition of P-gp efflux
    pump in various cell cultured mediums. [28]

Ø PEG Based Detergents

  • Various studies confirmed that polymeric surfactants including D-alpha-tocopheryl polyethylene glycol succinate 1000, polysorbates as well as POE
    stearate and alkyl-PEO surfactants are capable of inhibiting P-gp efflux pumps.
  • The mechanism to inhibit P-gp by these polymeric surfactants is believed to be mediated by modifying the function of cell membrane lipid.

Ø D-α-Tocopheryl polyethylene glycol succinate 1000(TPGS 1000):

  • TPGS 1000 has been widely used as an emulsifying agent, solubilizer and drug delivery based on lipids.
  • By the application of TPGS-1000, Researcher has improved the absorption of BCS class IV drugs and of Paclitaxel due to enhancement in solubility
    and inhibition of P-gp efflux action.
  • P-gp inhibition by TPGS-1000 is due to influence of its length of alkyl chain of various TPGS derivatives. TPGS-1000 is believed to be most
    powerful inhibitor of P-gp amongst all TPGS derivatives. [29]

Ø Polysorbates:

  • Polysorbates are widely marketed under the brand name of Tween®. Various researches confirmed capacity of Tween® 20, Tween® 40, and Tween® 80 to
    inhibit efflux pumps.
  • Researcher has improved absorption of daunorubicin in tumor tissue with application of 0.01% Tween® 80. [30]
  • In one more study, by the use of Tween 80 with P-gp model drug Rhodamine 123 showed that P-gp efflux pump action was minimized.

    [31,32,33,34]

  • Ø

    Poloxamers:

    • It is widely known as Pluronics®.

      [35,36]

    • Pluronic P85 has been comprehensively investigated for P-gp inhibitory activity.
    • P-gp efflux pump inhibition by Pluronics is due to (a) Reduction of ATP and inhibition of ATPase and (b) effects of fluidization of cell membrane
      lipid. [37,38]
    • P-gp efflux pump inhibition by Pluronics is mainly targeted in two regions:

    o Blood Brain Barrier (BBB) and

    o Chemotherapy.

    • One of the main reason of enhanced Cytotoxicity of chemotherapeutic agent is due to presence of Pluronics that inhibit P-gp. [39,40,41]
    • Researchers have reported that Pluronics also inhibits MRP1 (Multidrug Resistant Protein) and MRP2, But Pluronics more specifically acting on P-gp
      ATPase than MRP1 and MRP2 ATPase. This is shown in Table 3. [42]
    • So, Pluronics are potential excipient in chemotherapy because it affects drug complexation process and their metabolic pathways.

    Table 3: Effect of Pluronic P85 on the permeability of P-gp and MRP through Brain Microvessel Endothelial Cell (BMVEC) Monolayers [42]

    Efflux Pump Substrate

    Efflux Pump

    Enhancement Ratio

    Methotrexate

    MRP

    1.3

    Fluoresin

    MRP

    1.5

    Rhodamine 123

    P-gp

    1.6

    Zidovudine

    MRP

    2.0

    Doxorubicin

    P-gp, MRP

    2.4

    Digoxin

    P-gp

    4.1

    Ritonavir

    P-gp

    7.7

    Paclitaxel

    P-gp

    11.2

    Vinblastin

    P-gp, MRP

    19.0

    (Where MRP is Multidrug Resistant Protein)

    Ø POE Stearates (Myrj) and Alkyl-PEO Surfactants (Brij): At 0.5% concentration, these having analogous mechanisms as that of poloxamers.

    • Researchers have shown that in various cell cultured medium, there is enhanced absorption of Epirubicin with application of POE 40 Stearates and
      also it reduces efflux ratio. When using polyoxyethylene laurylether (Brij® 30), analogous results were obtained to that of POE 40 Stearates. [32]

    Ø Thiomers:

    • These polymers have been newly launched and implemented in the pharmaceutical area.
    • Polymers having thiol group has shown to have superior bioadhesive, enzyme inhibitory and penetration improving properties. [43]
    • Recently, Many Researchers have suggested that Thiomers is having P-gp pump inhibitory activity due to thiol group. [44]
    • Because Thiomers form disulfide bond between cysteine group of P-gp and free thiol group of thiomers. [48]
    • For example:

    α-Chitosan–thiobutylamidine (chito– TBA),

    β-poly (acrylic acid)-cysteine (PAA-Cys)

    • There is no data available for P-gp inhibitory activity of Carbopol and unmodified Chitosan. [45,46,47]

    6.3 Nanocarrier drug delivery system:

    6.3.1 Liposomes:

    Liposomes are vesicles made up of bilayer or multilayers that contain phospholipids and cholesterol enveloping
    hydrophilic aqueous region. Both lipophilic and hydrophilic drugs can be encapsulated within this nanocarrier and is available for absorption at the
    intestinal membrane surface.

    Liposomes capable of modulating P-gp:

    Anionic Liposomes composed of anionic phospholipids such as Cardiolipin and Phosphatidylserine enhances cellular absorption and cellular toxicity as
    compared to free drugs when administered. These all due to P-gp inhibition by anionic phospholipid as these lipids directly interact with P-gp pump and
    also reported that higher cellular absorption occurs with application of Anionic liposomes. [50,51,52,53,54]

    If liposomes get penetrated into the cell, anionic liposomes release the drug intracellularly to overcome P-gp. [55] However, Anionic
    liposomes having very low Invivo shelf-life. But at present, many researches are on the way to increase its stability by approaching proper formulation
    design.

    Neutral phospholipids like Phosphatidylethanolamine (PE) and Phosphatidylcholine (PC) are selectively effluxed out by P-gp so there would be
    competition for P-gp when neutral phospholipids administered with P-gp substrates. [56,57,58]

    For example, liposomes composed of PC or PE enhances drug accumulation and these happen not only with liposome entrapped drug but also with liposomes
    without drug that is all due to interaction between cell membrane and liposomes. [59]

    Combining liposomes and P-gp efflux inhibitors:

    Many P-gp inhibitors have been came across but none succeeded to get FDA approval due to inappropriate clinical results and
    benefits. One of the major reason is P-gp inhibitors have their own pharmacological action or toxicity when they are combined with our desired drug.

    For example, PSC 833 (Valspodar) is powerful inhibitor of P-gp, having very little toxicity but when combined with
    chemotherapeutic agent, it alters pharmacokinetic and pharmacodynamic properties of chemotherapeutic agent and lead to unpredictable bioavaibility. [60,61]

    In clinical trials, liposomes encapsulated PSC 833 with doxorubicin did not show any undesirable pharmacokinetic and
    pharmacodynamic alteration. [62,63,64,65]

    Table 4: Various ways to bypass P-gp using various kind of Liposomal approach[49]

    Types

    Action

    Anionic Liposomes

    •contain Anionic Phospholipid; Cardiolipin or Phosphatidylserine that may inhibit P-gp by interaction with membrane lipids.

    Stimuli Responsive Liposomes

    •These types of Liposomes trigger the release based on response in terms of pH change, Temperature change or any other stimuli.

    Liposomes and

    P-gp inhibitor combination

    •These will inhibit P-gp and successfully deliver our desired drug candidate

    Delivery of hydrophobic drug analogs

    •Liposomes successfully releases the hydrophobic drugs that are not effluxed by P-gp

    Gene therapy approaches

    •can be used to bypass P-gp or to prevent drug resistance

    6.3.2 Stealth liposome carriers:

    They contain Cholesterol, Hydrogenated Soy Phosphatidylcholine and PEGylated Phosphoethanolamine.

    For example, Agents available in market are:

    • PEGylated liposomal doxorubicin (Doxil® ALZA Pharmaceuticals, Palo Alto, CA; also recognized as Caelyx®)-It has tremendously improved Invivo
    half-life and enhanced accumulation in the tumor tissue. [66]

    • Liposomal daunorubicin (DaunoXome®, Gilead Sciences, Foster City, CA) [67]

    • Liposomal doxorubicin (MyocetTM, Elan Pharma, Munich, Germany) [68]

    • Cytarabine liposomes (DepoCyt)

    6.3.3 Niosomes :

    Niosomes are in which medication is encapsulated in vesicles and these vesicles composed of Non-ionic Surfactant Vesicles hence it is called as
    Niosomes, having a similar kind of mechanism as that of liposomes.

    6.3.4 Polymeric nanoparticles:

    Various polymers used to prepare nanoparticles include poly (methylidene malonate), poly (alkylcyanoacrylates), and polyesters such as poly
    (e-caprolactone), poly (lactic acid), poly (glycolic acid), and their copolymers. Nanoparticles showed to bypass P-gp due to their nanometer size
    range.

    6.3.5
    Dendrimers:

    Dendrimers are polymer of 21st century. It is defined as macromolecule which is characterized by its highly branched 3-D structure that
    provides high degree of surface functionality and versatility.

    Polyamidoamine (PAMAM) dendrimer:
    Its mechanism to inhibit P-gp pump is not still clearly investigated. But some researchers have suggested that via endocytosis, dendrimer get
    penetrated into the cell. So, P-gp inhibition may be due to alteration of cell membrane function, ATPase inhibition or ATP reduction.

    Many researches demonstrated that dendrimer encapsulated P-gp substrates showed higher intracellular accumulation in comparison to substrates without
    application of dendrimer.

    Absorption of doxorubicin and Vinblastine in GIT was improved by 3 to 4 times by application of G-3 dendrimer; it may be due to P-gp inhibition.[24]

    6.4 Polymer–drug conjugates:

    Ø Albumin conjugated with Paclitaxel, Ambraxane approved in 2005 by FDA for patients with breast cancer as a second-line treatment.
    [69]

    Ø Polymer used to make conjugation with drug is N-(2-hydroxypropyl) methacrylamide (HPMA).

    PNU166945 (HPMA copolymer–Paclitaxel)

    FCE28069 (HMPA copolymer–doxorubicin-galactosamine) under clinical trials.

    Mechanism of Polymer-Drug Conjugate

    Figure 4: Mechanism of Polymer-Drug Conjugate. [69]

    Where Dox – Doxorubicin

    7. Future Prospects:-

    1) Acid and Base Sensitive Nanohydrogels for Glioblastoma.

    2) pH Sensitive Liposomes which at Acidic pH fused with cancer cell and at physiological pH repelled with normal cell.

    3) Self Emulsifying Drug delivery systems may be useful to bypass P-gp efflux pump because of presence of surfactants like Tween 80, SLS, Dialkyl
    sulfosuccinate etc. [70, 71]

    8. Conclusion:-

    P-gp influences pharmacokinetic and pharmacodynamic property of various drugs. The existence of P-gp in the blood-brain barrier (BBB) limits the entry
    of drug to CNS as drugs are effluxed out by P-gp from CNS. Same way, P-gp is also present over GI tract which limits gastrointestinal absorption of
    substrate drugs. Central nervous system entry of some drugs can be improved by blocking P-gp activity and enhances efficacy and oral bioavaibility. The
    role of P-gp and the MDR1 gene should be well investigated in different species and a relationship between the protein presence or absence and the
    pharmacokinetic and pharmacodynamic properties of drugs should be determined.

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    About Authors:

    Dr. Mukesh C. Gohel, Dr. Rajesh K. Parikh, Sanjay C. Modi, Kalpesh G. Vyas, Krushit M. Sheth

    L. M. College of Pharmacy, Ahmedabad, Gujarat, India.

    Dr. Mukesh C. Gohel

    Dr. Mukesh C. Gohel

    Dr. Rajesh K. Parikh

    Dr. Rajesh K. Parikh

    Sanjay C. Modi

    Sanjay C. Modi

    Kalpesh G. Vyas

    Kalpesh G. Vyas

    Krushit M. Sheth

    Krushit M. Sheth

    Volumes and Issues: 
    Reviews: 

    4 Comments

    sanjaypatel's picture
    sanjaypatel says:
    Dear sir Thanks for one more informative article.
    Sanjay Patel M.Pharm, LL.B (Continue) Indian Patent Agent patentagent2007@gmail.com
    Submitted by sanjaypatel on Fri, 06/03/2011 - 04:51
    tasneemara's picture
    tasneemara says:
    kudos!!!!!just an excellent research paper.keep it up sir.congratulations to all the research team.
    Submitted by tasneemara on Sun, 09/04/2011 - 05:48
    Vivek Patel's picture
    Vivek Patel says:
    Dear Sir, It's a good informative review. Thanks Sir !!!
    Vivek Patel Research Scientist, Sun Pharmaceutical Ind. Ltd., Vadodara.
    Submitted by Vivek Patel on Mon, 06/13/2011 - 05:27
    Prof. J. Vijaya Ratna's picture
    Dear Sir I congratulate you on this very informative article. Please comment on foods that inhibit P-gp and foods that induce P-gp. Vijaya Ratna
    Submitted by Prof. J. Vijaya... on Mon, 08/15/2011 - 16:33