Drug transporters

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Drug Transporters

Transcript of Drug transporters

  1. 1. Drug Transporters
  2. 2. Introduction Types of transport Role of transporters Regulation of transporters on genetic level ABC Superfamily P glycoprotein SLC transporters OAT/OCT Hepatic transporters Renal transporters
  3. 3. A pt comes to you with chief complaints of diarrhoea. He is a known case of arrhythmias on quinidine. You advice him to take loperamide. After taking the drug , he goes into respiratory depression. What do you think happened?
  4. 4. transport Carrier mediated Active primary secondary Facilitated Non carrier mediated Passive
  5. 5. Transport Ion Channels Transporters Aquaporins
  6. 6. Aquaporins bi-directional membrane channels -transport water not ion channels- H2O is transported as an uncharged molecule driving force-osmotic gradient 13 AQP genes in the human genome
  7. 7. Transporters It forms an intermediate state with the substrate Turnover is 101 to 103 s saturable Channels They occur in an open and closed state Turnover is 106 to 108 s1 Non saturable
  8. 8. Transporters membrane proteins control influx of essential nutrients and ions efflux of cellular waste, environmental toxins, drugs, and other xenobiotics coded by 7% of the total number of genes
  9. 9. Physiological Role of Transporters Regulates the distribution and bioavailability of drugs Removal of toxic metabolites and xenobiotics from cells into urine,bile and intestinal lumen Transport of compounds out of the brain across the blood brain barrier
  10. 10. Types of membrane transporters 2000 genes in humans code for transporters or transporter related proteins 2 major superamilies- ABC and SLC Most ABC proteins are primary active transporters SLC superfamily includes facilitated transporters and ion coupled secondary active transporters
  11. 11. ABC 49 genes- classified into 7 families unidirectional Widely recognised are P- glycoprotein and CFTR SLC 48 families with 315 transporters bidirectional SERT encoded- SLC6A4 DAT encoded- SLC6A3
  12. 12. Vectorial transport
  13. 13. What does the term vectorial imply?? Transport of an ion or molecule across an epithelium in a certain direction (e.g. absorption of glucose by the gut). Vectorial transport implies a nonuniform distribution of transport proteins on the plasma membranes of two faces of the epithelium.
  14. 14. Regulation of transporter expression
  15. 15. Following receptors form heterodimers with 9 cis- retinoic acid receptors Pregnane X receptor (PXR) Peroxisome proliferator activated receptor (PPAR) Retinoic Acid Receptor (RAR) Farnesoind X Receptor (FXR)
  16. 16. Pregnane X Receptor Activated by 1.Phenobarbitone 2.Rifampicin 3.Carbemezapine 4.Phenytoin
  17. 17. ATP Binding Cassette Transporter protein superfamily Transmembrane proteins utilize the energy of ATP hydrolysis 48 ABC genes in humans Can be divided into 7 groups
  18. 18. Functions ABC Importers Cell viability pathogenesis Exporters Translation and repair
  19. 19. Structure The common structure of all ABC consists of 2 Distinct domains Transmembrane domain (TMD) Nucleotide binding Domain (NBD)
  20. 20. In most Exporters- the N terminal TMD and C terminal NBD are fused to form a single polypeptide chain arranged as TMD-NBD-TMD-NBD Importers- have an inverted organisation- NBD-TMD- NBD-TMD where the ABC domain is N- terminal whereas the TMD is C terminal
  21. 21. ABC EXPORTER
  22. 22. GENE NAME FAMILY NAME NO. OF FAMILIES DIS. ASOCIATED ABCA ABC A 12 Tangiers dis Stargadts dis ABCB ABC B 11 PFIHC ABCC ABC C 13 Cystic fibrosis Dubin Johnson syn ABCD ABC D 4 Adreno-leukodystrophy ABCE ABC E 1 ABCF ABC F 3 ABCG ABC G 5 Sitosterolemia
  23. 23. Dubin Johnson syndrome
  24. 24. Dubin Johnson syndrome
  25. 25. SLC Transporters Includes 48 families and represents 315 genes in human genome Contain hydrophobic transmembrane alpha helices Includes facilitative transporters and secondary active transporters
  26. 26. Nomenclature SLCnXm : SLC : root name n: family X: subfamily m: isoform
  27. 27. Intestinal Transporters
  28. 28. Various transporters are expressed on the brush border of the intestine Influx transporters expressed In the gut, improve absorption eg. PEPT-1, OATB1 PEPT1- mediates transport of drugs- B-Lactams, ACEI, Valacyclovir Efflux transporters limit the absorption of drugs eg. P gp, BCRP, MRP2
  29. 29. BCRP member of the ABC Transporter family Plays role in secretion of topotecan When topotecan, substrate for BCRP and GF120918( ELACRIDAR), an inhibitor of both BCRP and P gp were administered orally, bioavailability of topotecan was increases in P- gp deficient mice
  30. 30. BCRP Is expressed also in the bile canalicular membrane and placenta In pregnant GF120918 Treated P gp deficient mice,fetal penetration of topotecan was 2 fold higher
  31. 31. Oral drug inhibitor transporter Digoxin quinidine P gp Paclitaxel Cyclosporin P gp methotrexate Omeprazole BCRP irinotecan gefitinib BCRP
  32. 32. Hepatic transporters
  33. 33. Statins are substrate for uptake transporters Uptake transporter- OATP1B1 Efflux transporter- MRP2
  34. 34. Temocapril Temocaprilat- excreted in both bile and urine Plasma concentration of temocaprilat remains unchanged even in patients of renal failure Temacoprilat is a bisubstrate of OATP and MRP2, whereas other ACEI are not good substrates of MRP2
  35. 35. IRINOTECAN CPT-11 SN-38 Glucuronide conjugation Excreted in bile by MRP-2 DIARRHOEA PROBENECID
  36. 36. Renal Transporters Renal transporters play an important role in drug elimination ,toxicity and response Transporters may have dual specificity for organic anions and cations
  37. 37. Endogenous Choline Dopamine Exogenous Cimetidine Ranitidine Metformin procainamide
  38. 38. Organic Anion Transporters Weak acidic drugs like 1. Pravastatin 2. Captopril 3. Penicillin
  39. 39. Na KG K OA KG
  40. 40. Organic anion transport
  41. 41. Role in CNS Involved in neuronal reuptake- SLC1 and SLC6 SLC6 responsible for reuptake of 1. norepinephrine 2. dopamine 3. serotonin 4. GABA
  42. 42. SLC6A1 /GAT1- Target for the drug tigabine SLC6A2/NET - Target for despramine SLC6A3/DAT- cocaine and its analogs SLC6A4/SERT- Target for fluoxetine and paroxetine
  43. 43. Role of transporters in drug resistance
  44. 44. In 1976, Ling reported the overexpression of a membrane protein in colchicine resistance Chinese hamster ovary cells, acquired resistance to various other drugs!!
  45. 45. Q.1. What is the genetic basis??? Q.2. How frequency will it occur?????
  46. 46. Hypothesis If a drug resistance occurs at rate of 10-7 Resistance to 2 unrelated drugs 10 -14 Shouldnt that be very rare????
  47. 47. P glycoprotein
  48. 48. 170 kDa transmembrane glycoprotein ATP-dependent drug efflux pump responsible for decreased drug accumulation mediates the development of resistance to anticancer drugs also functions as a transporter in the BBB
  49. 49. P gp in humans MDR1 Responsible for efflux of drugs MDR2 Transport of phosphatidylcholine to bile
  50. 50. Epithelial cells : Colon intestine Pancreas Kidney Adrenals Endothelial cells brain
  51. 51. Models of action of P gp
  52. 52. PUMP MODEL
  53. 53. VACUUM MODEL
  54. 54. FLIPPASE MODEL
  55. 55. SUBSTRATES Analgesics Morphine Antibiotics Tetracycline, Rifampicin Anticancer Etoposide,Vincristine, Daunorubicin Antiemetics Ondansetron Antidepressants Venlafaxine Antifungals Itraconazole HIV Protease Inhibitors Saquinavir, Indinavir Antidiarrhoeal Loperamide Antiepileptics Phenytoin, Carbemazapine Cardiac glycosides Digoxin
  56. 56. DRUGS INHIBITORS Antiarrythmics Verapamil, Amiodarone Antibiotics Clarithromycin, Erythromycin Anticancer Actinomycin D, Vinblastine Calcium Channel Blockers Verapamil, Nifedipine Proton pump inhibitors Pantoprazole, Lansoprazole Antidepressants Sertraline Steroids Tamoxifen
  57. 57. Relation between Pgp and cyp3A4 Both are regulated by PXR P gp keeps intracellular concentration within the range of CYP3A4 Metabolism results In better substrates of P gp cyp3A4 P gp
  58. 58. PXR P gpCYP3A4
  59. 59. Transporters and drug resistance Play a critical role in developing resistance to Anti cancer Anti microbials Anti epileptics
  60. 60. Why resistance is so important to study? result in treatment failure increased costs, prolonged duration of hospital stay higher morbidity and mortality rates
  61. 61. How to over come this resistance?
  62. 62. Approaches to overcome MDR 1. REVERSAL AGENTS known as chemosensitisers inhibit P gp increase intracellular concentration of the drug
  63. 63. First generation agents Have their own pharmacological action Were used in high doses Not selective to P gp Therefore, high toxicity 1. Cyclosprine hepatic, renal, myeloid , neurotoxicity 2. Verapamil- cardiotoxicity
  64. 64. Second Generation Agents Selective and less toxic Substrates of P gp and CYP3A4 Lead to unpredictable absorption and metabolism 1. Valspodar ( R enantiomer of verapamil) 2. Biricodar
  65. 65. Third generation agents Agents were not substrates of CYP3A4 Selectively and potentially inhibit Pgp 1. Tariquidar XR9576 2. Zosuquidar LY335979 3. Laniquidar R101933
  66. 66. Newer ways to overcome MDR Monoclonal Ab- MRK 16- reversed MDR in transgenic mice Epothilones- not recognised by P gp Increase rate of influx of anticancer drug by increasing lipophilicity of the compound
  67. 67. So why do we need these transporters??? To regulate bioavailability To act as drug targets To eliminate toxins To overcome resistance
  68. 68. Involvement of a transporters is more of a rule than an exception!!!!