Drugs transporters


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importance of membrane transporters in the field of pharmacology

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Drugs transporters

  1. 1. Prepared by Alaa Ibrahim Assistant lecturer of clinical pharmacology Under supervision of Pro.Dr. Sohair El Menshawy Prof. of clinical Pharmacology11/18/2012 Transporters 1
  2. 2.  1- Introduction 2- Types of Transporters 3- Structure of Transporters 4- Mechanism of Action Of Transporters 5- Regulation of Transporter Expression 6- Physiological & Pharmacological role of Transporters 7- Novel Approaches To Bypass Drug Transporters11/18/2012 Transporters 2
  3. 3.  The basic mechanisms involved in solute transport across biological membranes include passive diffusion, facilitated diffusion, and active transport Active transport can be further subdivided into primary and secondary active transport.11/18/2012 Transporters 3
  4. 4. 11/18/2012 Transporters 4Mechanism of membrane permeation
  6. 6.  Secondary active transport ( co-transport): uses energy to transport molecules across a membrane. In contrast to primary active transport, there is no direct coupling of ATP; instead, the electrochemical potential difference created by pumping ions out of the cell is used.The two main forms of this are1- antiport: Na+ Ca++ exchanger2- symport: glucose symporter which co- transports one glucose molecule into the cell for every two Na+11/18/2012 Transporters 6
  7. 7. Types of 2ry Active Transporters11/18/2012 Transporters 7II- Symbort ( co-transport)III- Antiport ( exchange)
  8. 8. Types of Membrane Transporters 8 2000 genes in the human genome (7% of the total number of genes) code for transporters or transporter-related proteins. In considering the transport of drugs, pharmacologists generally focus on transporters from two major superfamilies, ABC (ATP binding cassette) and SLC (solute carrier) transporters Most ABC proteins are primary active transporters, which rely on ATP hydrolysis to actively pump substrates across membranes The SLC superfamily includes genes that encode facilitated transporters and ion-coupled secondary active transporters Transporters 11/18/2012
  9. 9. ABC (ATP binding cassette) 49 known genes for ABC  48 SLC families with 315 proteins that can be transporters have been identified in the human grouped into 7 subclasses genome or families (ABCA to  Many serve as drug targets ABCG) or in drug absorption and the best recognized in the disposition ABC superfamily are P-  Widely recognized SLC glycoprotein (P-gp, transporters include the encoded by ABCB1, also serotonin (5-HT) and termed MDR1) and the dopamine transporters cystic fibrosis (SERT, encoded by transmembrane regulator SLC6A4; DAT, encoded by (CFTR). SLC6A3). Transporters 11/18/2012 9
  10. 10. Structure of ABC Transporters Transporters 11/18/2012 10
  11. 11.  The common feature of all ABC transporters is that they consist of two distinct domains, the transmembrane domain (TMD) and the nucleotide-binding domain (NBD). The TMD, also known as membrane-spanning domain (MSD) or integral membrane (IM) domain, consists of alpha helices, embedded in the membrane bilayer. It recognizes a variety of substrates and undergoes conformational changes to transport the substrate across the membrane. The sequence and architecture of TMDs is variable, reflecting the chemical diversity of substrates that can be translocated. Transporters 11/18/2012 11
  12. 12.  The NBD or ATP-binding cassette (ABC) domain, on the other hand, is located in the cytoplasm and has a highly conserved sequence. The NBD is the site for ATP binding. In most exporters, the N-terminal transmembrane domain and the C-terminal ABC domains are fused as a single polypeptide chain, arranged as TMD-NBD- TMD-NBD. Importers have an inverted organization, that is, NBD- TMD-NBD-TMD, where the ABC domain is N-terminal whereas the TMD is C-terminal Transporters 11/18/2012 12
  13. 13. Structure of ABC Transporters Transporters 11/18/2012 13
  14. 14. Structure of ABC Transporters Transporters 11/18/2012 14
  15. 15.  Some ABC transporters have additional regulatory class of proteins. In particular, importers have a high- affinity binding protein (BP) that specifically associates with the substrate in the periplasm for delivery to the appropriate ABC transporter Exporters do not have the binding protein but have an intracellular domain (ICD) that joins the membrane-spanning helices and the ABC domain. The ICD is believed to be responsible for communication between the TMD and NBD Transporters 11/18/2012 15
  16. 16.  The structural architecture of ABC transporters consists minimally of two TMDs and two ABCs. Most exporters, such as in the multidrug exporter are made up of homodimer consisting of two half transporters A full transporter is often required to gain functionality Transporters 11/18/2012 16
  17. 17.  ABC transporters are active transporters, they require energy in the form of (ATP) to translocate substrates across cell membranes. These proteins harness the energy of ATP binding and/or hydrolysis to drive conformational changes in the transmembrane domain (TMD) and consequently transports molecules.  Both ABC importers and exporters have a common mechanism in transporting substrates because of the similarities in their structures.11/18/2012 Transporters 17
  18. 18. 11/18/2012 Transporters 18
  19. 19.  In this model, the substrate binding site alternates between outward- and inward-facing conformations. The relative binding affinities of the two conformations for the substrate largely determines the net direction of transport. For importers, since translocation is directed from the periplasm to the cytoplasm, then the outward-facing conformation will have higher binding affinity for substrate. In contrast, the substrate binding affinity in exporters will be greater in the inward-facing conformation.11/18/2012 Transporters 19
  20. 20. 11/18/2012 Transporters 20
  21. 21.  This model presents two principal conformations of the NBDs: formation of a closed dimer upon binding two ATP molecules and dissociation to an open dimer facilitated by ATP hydrolysis and release of inorganic phosphate (Pi) and adenosine diphosphate (ADP). Switching between the open and closed dimer conformations induces conformational changes in the TMD resulting in substrate translocation11/18/2012 Transporters 21
  22. 22.  Regulating the distribution and bioavailability of drugs  The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen  The transport of compounds out of the brain across the blood–brain barrier  Protection of hematopoietic stem cells from toxins11/18/2012 Transporters 22
  23. 23. Regulation of TransporterExpression Transcription of transporter mRNAs changes in response to drug treatment and pathophysiological conditions, resulting in induction or down regulation. Recent studies have described important roles of type II nuclear receptors, which form heterodimers with the 9-cis-retinoic acid receptor (RXR), in regulating drug-metabolizing enzymes and transporters11/18/2012 Transporters 23
  24. 24.  Such receptors include pregnane X receptor ( PXR), constitutive androstane receptor (CAR) ,farnesoid X receptor (FXR)& PPARα (peroxisome proliferator-activated receptor α) and retinoic acid receptor (RAR) These are ligand-activated nuclear receptors that, as heterodimers with RXR, bind specific elements in the enhancer regions of target genes.  There is an overlap of substrates between CYP3A4 and P-glycoprotein, and PXR mediates coinduction of CYP3A4 and P-glycoprotein, supporting their synergetic cooperation in11/18/2012 Transporters 24
  25. 25. 11/18/2012 Transporters 25
  26. 26. Transporters 26 11/18/2012
  27. 27.  Role of Transporters in Drug Absorption 11/18/2012 Transporters 27
  28. 28.  Various transporters are expressed in the brush-border membranes of intestinal epithelial cells involved in the efficient absorption of nutrients or endogenous compounds. The influx transporters expressed in the gut improve drug absorption Example: PEPT1, ASBT, OATP-B, OATP-D & OATP-E PEPT1 mediates the transport of peptide-like drugs such as β-lactam antibiotics, ACEIs inhibitors and the dipeptide-like anticancer drug bestatin 11/18/2012 Transporters 28
  29. 29.  However efflux transporters, such as P-gp, MRP2, or BCRP, are expressed on the brush-border membrane of enterocytes and excrete their substrates into the lumen, resulting in limitation of net absorption Activesecretion of absorbed drug is now is now Active secretion of absorbed drug becoming becomingas a significantas a significant factor recognized recognized factor in oral drug bioavailability in oral drug bioavailability P-gp affects the absorption of many drugs because of its broad substrate specificity The intestinal P-gp content correlates with the AUC after oral administration of digoxin, a P-gp substrate 11/18/2012 Transporters 29
  30. 30. Schematic of role of P-gp intestinal disposition of substrate.11/18/2012 Transporters 30
  31. 31.  A report involving a patient undergoing a small bowel transplant demonstrated that plasma conc. of oral tacrolimus, a substrate of both P-gp and CYP3A4, correlated well with the mRNA expression of intestinal MDR1, but not CYP3A4 These results suggest that intestinal P-gp, rather than CYP3A4, is a good probe to predict intraindividual variations in tacrolimus pharmacokinetics. 11/18/2012 Transporters 31
  32. 32.  BCRP is a member of the ABC transporter family has only one ATP-binding cassette and six transmembrane domains, suggesting that BCRP is a half-transporter, which may function as a homo- or heterodimer. BCRP plays a role in the secretion topotecan When both topotecan, a substrate of BCRP, and GF120918, an inhibitor of both BCRP and P-gp, were administered orally, the bioavailability of topotecan was increased in P-gp-deficient mice (over 6-fold) compared with mice given vehicle alone 11/18/2012 Transporters 32
  33. 33.  BCRP is expressed not only in the intestine, but also in the bile canalicular membrane and placenta .Thus, treatment with GF120918 reduced the plasma clearance and hepatobiliary excretion of topotecan . Furthermore, in pregnant GF120918-treated, P-gp- deficient mice, the fetal penetration of topotecan was 2-fold higher than that in pregnant mice given vehicle alone. These results indicate that BCRP plays an important role in protecting the fetus from topotecan. 11/18/2012 Transporters 33
  34. 34. 11/18/2012 Transporters 34
  35. 35.  Hepatic uptake of organic anions (e.g., drugs, LTs and bilirubin), cations, and bile salts is mediated by SLC-type transporters in the basolateral (sinusoidal) membrane of 11/18/2012 hepatocytes: 1- OATPs (SLCO) and OATs (SLC22) for anions Transporters 2- OCTs and NTCP (SLC10A1) for cations & bile salts This uptake either by facilitated or secondary active mechanisms ABC transporters such as MRP2, MDR1, BCRP, BSEP, and MDR2 in the bile canalicular membrane of hepatocytes mediate the efflux (excretion) of drugs and their metabolites, bile salts, and phospholipids against a 35 steep concentration gradient from liver to bile. This primary active transport is driven by ATP hydrolysis
  36. 36. 11/18/2012 Transporters 36VECTORIAL TRANSPORT
  37. 37.  Vectorial transport of drugs from the circulating 11/18/2012 blood to the bile using an uptake transporter (OATP family) and an efflux transporter Transporters (MRP2) is important for determining drug exposure in the circulating blood and liver. Different examples illustrate the importance of vectorial transport in determining drug exposure in blood & liver: 37
  38. 38. 1- HMG-CoA Reductase Inhibitors: 11/18/2012 Statins are cholesterol-lowering agents that reversibly inhibit HMG-CoA reductase Transporters enzyme inhibit cholesterol biosynthesis mainly in the liver ( the main target), while exposure of extrahepatic cells in smooth muscle to these drugs may cause adverse effects Pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin are given in a biologically active open-acid form 38 (relatively hydrophilic and have low membrane permeability)
  39. 39.  However, most of the statins in the acid form are substrates of uptake transporters, so they are taken up efficiently by the liver 11/18/2012 and undergo enterohepatic circulation So, hepatic uptake transporters such as Transporters OATP1B1 and efflux transporters such as MRP2 act cooperatively to produce vectorial transcellular transport of bisubstrates in the liver The efficient first pass hepatic uptake of statins by OATP1B1 after their oral administration helps to exert the pharmacological effect and also minimizes the escape of drug molecules into the 39 circulating blood limiting systemic adverse effects
  40. 40. 2- Temocapril is an ACE inhibitor Itsactive metabolite, temocaprilat, is excreted both in the bile and in the urine 11/18/2012 whereas other ACE inhibitors are excreted mainly via the kidney. Transporters The special feature of temocapril among ACE inhibitors is that the plasma concentration of temocaprilat remains relatively unchanged even in patients with renal failure. Temocaprilat is a bisubstrate of the OATP family and MRP2, whereas other ACE inhibitors are not good substrates of MRP2 40
  41. 41.  Taking these findings into consideration, the affinity for MRP2 may dominate in determining the biliary excretion of any 11/18/2012 series of ACE inhibitors. Transporters Drugs that are excreted into both the bile and urine to the same degree thus are expected to exhibit minimum interindividual differences in their pharmacokinetics. 41
  42. 42. 3-Irinotecan (CPT-11): isa potent anticancer drug, but late-onset 11/18/2012 gastrointestinal toxic effects, such as severe diarrhea, make it difficult to use CPT-11 Transporters safely. Afterintravenous administration, CPT-11 is converted to SN-38, an active metabolite, by carboxy esterase. SN-38 is subsequently conjugated with glucuronic acid in the liver. SN-38 and SN-38 glucuronide are then excreted into the bile by MRP2. 42
  43. 43.  Some studies have shown that the inhibition of MRP2-mediated biliary excretion of SN-38 and its glucuronide by coadministration of 11/18/2012 probenecid reduces the drug induced diarrhea, at least in rats. Transporters Itis expected that this agent will be used clinically to prevent toxicity. Approaches using intentional drug-drug interactions (positive drug interactions) like this case may become more important in the future 43
  44. 44. 4- Troglitazone:A thiazolidinedione insulin-sensitizing agent 11/18/2012 for the treatment of NIDDM Was withdrawn from the market because of Transporters liver toxicity . the mechanism underlying this troglitazone-associated hepatotoxicity is at present unclear, but it has been suggested that a cholestatic mechanism is involved Troglitazone and, to a much greater extent troglitazone sulfate, the main troglitazone metabolite eliminated into bile, competitively inhibit ATP-dependent taurocholate transport 44 via BSEP
  45. 45.  This inhibition of the hepatobiliary export of bile salts by troglitazone and troglitazone sulfate may lead to a drug-induced intrahepatic cholestasis 11/18/2012 possibly contributing to their hepatotoxicity Cholestasis induced by some drugs is mediated, Transporters at least in part, by inhibition of BSEP, resulting in intracellular accumulation of cytotoxic bile salts. For examples: cyclosporine, rifampicin, glibenclamide & the cholestatic estrogen metabolite One should consider the possibility that drugs which inhibit BSEP may cause cholestasis The evaluation of BSEP inhibition will play an important role in the identification of compounds 45 that could be a potential cause of cholestasis.
  46. 46. Transporters 11/18/2012 46
  47. 47.  During the past decade, molecular studies have identified and characterized the renal transporters that play a role in drug elimination, toxicity and response. we now can describe the overall secretory pathways for organic cations and their molecular and functional characteristics Our understanding of organic anion transport has progressed in a similar fashion. In some cases, transporters that are considered organic anion or organic cation transporters have dual specificity for anions and cations Transporters 11/18/2012 47
  48. 48. Transporters 11/18/2012 48
  49. 49.  The OCT family of proteins is involved in the uptake of organic cations into the liver or kidney from blood. OCT1 and OCT2 are expressed in epithelial cells of the kidney, liver, and intestine, and appear to be localized to the basolateral membranes of the cells These transporters mediate the uptake of a variety of organic cations, such as dopamine, choline, 1-methyl-4- phenylpyridinium (MPP+), N1- methylnicotinamide, TEA, and cimetidine ranitidine, metformin, procainamide, and Transporters 11/18/2012 49
  50. 50.  Organic cations cross the basolateral membrane by three distinct transporters in the SLC family 22 (SCL22): OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). Organiccations are transported across this membrane down their electrochemical gradient (–70 mV). Transportof organic cations from cell to tubular lumen across the apical membrane occurs via an electroneutral proton– organic cation exchange mechanism Transporters 11/18/2012 50
  51. 51.  Transportersassigned to the apical membrane are in the SLC22 family and termed novel organic cation transporters (OCTNs). In humans, these include OCTN1 (SLC22A4) and OCTN2 (SLC22A5). These bifunctional transporters are involved not only in organic cation secretion but also in carnitine reabsorption. OCT2 play a housekeeping role in neurons, taking up only excess concentrations of neurotransmitters. OCT2also involved in recycling of neurotransmitters by taking up breakdown 51 11/18/2012 Transporters
  52. 52. Transporters 11/18/2012 52
  53. 53.  The primary function of organic anion transporters is the removal of xenobiotics (include weak acidic drugs e.g. pravastatin, captopril, pencillins & toxins) Two primary transporters on basolateral membrane mediate the flux of organic anions from intestinal fluid to tubular cell : OAT1( SLC22A6) & OAT3 ( SLC22A8) organic anions are transported across the basolateral membrane against an electrochemical gradient in exchange with intracellular α-ketoglutarate, which moves down its concentration gradient Transporters 11/18/2012 53
  54. 54.  The mechanism responsible for the apical membrane transport of organic anions from tubule cell cytosol to tubular lumen remains controversial Some studies suggest that OAT4 may serve as the luminal membrane transporter for organic anions Other transporters that may play a role in transport across the apical membrane include MRP2 and MRP4,multidrug- resistance transporters in the ATP binding cassette family C (ABCC). Transporters 11/18/2012 54
  55. 55. DRUG ACTION IN THE BRAIN Transporters 11/18/2012 55
  56. 56. 56• Transporters involved in the neuronal reuptake Transporters 11/18/2012 of the neurotransmitters and the regulation of their levels in the synaptic cleft belong to two major superfamilies, SLC1 and SLC6• Transporters in both families play roles in reuptake of γ-aminobutyric acid (GABA), glutamate, and the monoamine neurotransmitters NA, 5-HT, and dopamine. These transporters may serve as pharmacologic targets for neuropsychiatric drugs.
  57. 57. 57• SLC6 family members in the brain involved in the Transporters 11/18/2012 reuptake of neurotransmitters into presynaptic neurons include the NA transporters (NET, SLC6A2), the dopamine transporter (DAT, SLC6A3), the serotonin transporter (SERT, SLC6A4), and several GABA reuptake transporters (GAT1, GAT2, and GAT3)• The SLC6A family regulate the concentrations and dwell times of neurotransmitters in the synaptic cleft• The extent of transmitter uptake also influences subsequent vesicular storage of transmitters.• The transporters can function in the reverse direction.
  58. 58. 58SLC6A1 (GAT1), SLC6A11 (GAT3), andTransporters 11/18/2012SLC6A13 (GAT2).• GAT1 is the most important GABA transporter in the brain, expressed in GABAergic neurons and found largely on presynaptic neurons• GAT3 is found only in the brain, largely in glial cells. GAT2 is found in peripheral tissues, including the kidney and liver, and within the CNS in the choroid plexus and meninges
  59. 59. 59 Transporters 11/18/2012• GAT1, GAT2, and GAT3 are approximately 50% identical in amino acid sequence• The presence of GAT2 in the choroid plexus and its absence in presynaptic neurons suggest that this transporter may play a primary role in maintaining the homeostasis of GABA in the CSF.• GAT1 and GAT3 are drug targets.• GAT1 is the target of the antiepileptic drug tiagabine, which acts to increase GABA levels in the synaptic cleft of GABAergic neurons by inhibiting the reuptake of GABA.• GAT3 is the target for the nipecotic acid derivatives that are anticonvulsants.
  60. 60. 60 Transporters 11/18/2012• SLC6A2 (NET):• is found in central and peripheral nervous tissues as well as in adrenal chromaffin tissue• A major role of NET is to limit the synaptic dwell time of NA and to terminate its actions, salvaging NA for subsequent repackaging.• NET participates in the regulation of many neurological functions, including memory and mood.• NET serves as a drug target; the antidepressant desipramine is considered a selective inhibitor of NET.• Other drugs that interact with NET include other
  61. 61. 61 Transporters 11/18/2012• SLC6A3 (DAT)DAT is located primarily in the brain in dopaminergic neurons present mainly on presynaptic neurons at the neurosynapatic junction & also present along the neurons, away from the synaptic cleft.The primary function of DAT is the reuptake dopamine, terminating its actionsDAT is involved in functions like mood, behavior, reward, and cognitionDrugs that interact with DAT include cocaine, amphetamines, and the neurotoxin MPTP
  62. 62. 62 Transporters 11/18/2012• SLC6A4 (SERT)SERT is located in peripheral tissues and in the brain along extrasynaptic axonal membranesSERT clearly plays a role in the reuptake and clearance of serotonin in the brainSubstrates of SERT :1- 5-HT2- Tryptamine derivatives3- 3,4-methylene-dioxymethamphetamine (MDMA; ecstasy) neurotoxin4- Fenfluramine
  63. 63. 63• The serotonin transporter has been one of the Transporters 11/18/2012 most widely studied proteins in the human genome WHY ?1- It is the specific target of the antidepressants in the selective serotonin reuptake inhibitor class SSRI (e.g., fluoxetine and paroxetine)2- One of several targets of tricyclic antidepressants TCA (e.g., amitriptyline)3- The important role of 5-HT in neurological function and behavior, genetic variants of SERT have been associated with many behavioral and neurological disorders
  64. 64. 64 Transporters 11/18/2012• Membrane transporters play a critical role in the development of resistance to 1- anticancer drugs, 2- antimicrobial agents 3- anticonvulsants.• N.B) P-glycoprotein is overexpressed in tumor cells after exposure to cytotoxic anticancer agents• P-glycoprotein pumps out the anticancer drugs
  65. 65. 65 Transporters 11/18/2012• Other transporters, have been implicated in resistance to anticancer drugs include: 1- Breast cancer resistance protein (BCRP) 2- The organic anion transporters 3- several nucleoside transporters• N.B) The overexpression of multidrug-resistance protein 4 (MRP4) is associated with resistance to antiviral nucleoside analogs
  66. 66. 66 Transporters 11/18/2012• Tumors arising from tissues where MDR1P-gp is highly expressed show intrinsic resistance to different chemotherapeutic agents , although acquired resistance is often correlated with an increased expression of MDR1P-gpInhibition of P-gp represents a promising approach for treatment of multidrug-resistant tumors
  67. 67. I- Reversal agents:They are also called as chemosensitizers asthey inhibit P-gp efflux of drugs and increasethe absorption of drugs intracellularly so theseagents may be co-administered withtherapeutic agent as competitive inhibitors. Transporters 11/18/2012 67
  68. 68.  Reversalagents for P-gp as per the generation:A) First-generation agentsThese agents had their own pharmacological action.These agents were used in high dose as they were notselective to inhibit P-gp so they resulted into hightoxicity which impedes their use to inhibit P-gp:1- Cyclosporine: (hepatic, renal, myeloid andneurotoxicity)2- Verapamil: (cardiotoxicity) Transporters 11/18/2012 68
  69. 69. 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:1-Valspodar (R-enantiomer of Verapamil )2-Biricodar Transporters 11/18/2012 69
  70. 70. 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.1-Tariquidar XR95762- Zosuquidar LY3359793- Laniquidar R101933 Transporters 11/18/2012 70
  71. 71. II- Natural and Synthetic Polymers:A- Natural polymers:They are obtained from natural source. For example:1-Anionic gums:Xanthan gum P-gp inhibitor at 0.05%Gellan gum :P-gp inhibitors at 0.05%Dextran Xanthan gum :P-gp inhibitor at 0.05%2- From Green tea: Polyphenols3- From Grapefruit Juice: Various Polysaccharides like D-glucose and/or D-glucuronic acid Transporters 11/18/2012 71
  72. 72. B- 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, Dendrimers and Thiomers. The mechanism to inhibit P-gp by these polymeric surfactants is believed to be mediated by modifying the function of cell membrane lipid. Transporters 11/18/2012 72
  73. 73.  Thiomers: These polymers have been newly implemented in the pharmaceutical area. Polymers having thiol group has shown to have superior penetration improving properties. Recently, many researchers have suggested that thiomers is having P-gp pump inhibitory activity due to thiol group because thiomers form disulfide bond between cysteine group of P- gp and free thiol group of thiomers.For example: α-Chitosan–thiobutylamidine (chito– TBA) Transporters 11/18/2012 73
  74. 74.  III- Nanocarrier drug delivery system: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.Neutral phospholipids are selectively effluxed out by P-gp so there would be competition for P-gp when neutral phospholipids administered with P-gp substrates. Transporters 11/18/2012 74
  75. 75. CONCLUSION Transporters 11/18/2012 75
  76. 76.  Transportersare membrane proteins that are present in all organisms. These proteins control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, and other xenobiotics. The functions of membrane transporters may be facilitated (equilibrative, not requiring energy) or active (requiring energy). Drug-transporting proteins operate in pharmacokinetic and pharmacodynamic pathways, including pathways involved in both therapeutic and adverse effects Transporters 11/18/2012 76
  77. 77.  Membrane transporters play a critical role in the development of resistance to anticancer drugs, antiviral agents, and anticonvulsants. Variousapproaches have been developed to overcome the effect of membrane transporters include reversal agents, polymers & liposomes which could enhance the effect of substrate drugs of membrane transporters Transporters 11/18/2012 77
  78. 78. THANK YOU Transporters 11/18/2012 78