drug transporters
TRANSCRIPT
- 1. Drug Transporters
- 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. 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. transport Carrier mediated Active primary secondary Facilitated Non carrier mediated Passive
- 5. Transport Ion Channels Transporters Aquaporins
- 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. 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. 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. 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. 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. 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. Vectorial transport
- 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. Regulation of transporter expression
- 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. Pregnane X Receptor Activated by 1.Phenobarbitone 2.Rifampicin 3.Carbemezapine 4.Phenytoin
- 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. Functions ABC Importers Cell viability pathogenesis Exporters Translation and repair
- 19. Structure The common structure of all ABC consists of 2 Distinct domains Transmembrane domain (TMD) Nucleotide binding Domain (NBD)
- 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. ABC EXPORTER
- 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. Dubin Johnson syndrome
- 24. Dubin Johnson syndrome
- 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. Nomenclature SLCnXm : SLC : root name n: family X: subfamily m: isoform
- 27. Intestinal Transporters
- 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. 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. 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. Oral drug inhibitor transporter Digoxin quinidine P gp Paclitaxel Cyclosporin P gp methotrexate Omeprazole BCRP irinotecan gefitinib BCRP
- 32. Hepatic transporters
- 33. Statins are substrate for uptake transporters Uptake transporter- OATP1B1 Efflux transporter- MRP2
- 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. IRINOTECAN CPT-11 SN-38 Glucuronide conjugation Excreted in bile by MRP-2 DIARRHOEA PROBENECID
- 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. Endogenous Choline Dopamine Exogenous Cimetidine Ranitidine Metformin procainamide
- 38. Organic Anion Transporters Weak acidic drugs like 1. Pravastatin 2. Captopril 3. Penicillin
- 39. Na KG K OA KG
- 40. Organic anion transport
- 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. 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. Role of transporters in drug resistance
- 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. Q.1. What is the genetic basis??? Q.2. How frequency will it occur?????
- 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. P glycoprotein
- 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. P gp in humans MDR1 Responsible for efflux of drugs MDR2 Transport of phosphatidylcholine to bile
- 50. Epithelial cells : Colon intestine Pancreas Kidney Adrenals Endothelial cells brain
- 51. Models of action of P gp
- 52. PUMP MODEL
- 53. VACUUM MODEL
- 54. FLIPPASE MODEL
- 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. 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. 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. PXR P gpCYP3A4
- 59. Transporters and drug resistance Play a critical role in developing resistance to Anti cancer Anti microbials Anti epileptics
- 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. How to over come this resistance?
- 62. Approaches to overcome MDR 1. REVERSAL AGENTS known as chemosensitisers inhibit P gp increase intracellular concentration of the drug
- 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. 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. Third generation agents Agents were not substrates of CYP3A4 Selectively and potentially inhibit Pgp 1. Tariquidar XR9576 2. Zosuquidar LY335979 3. Laniquidar R101933
- 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. So why do we need these transporters??? To regulate bioavailability To act as drug targets To eliminate toxins To overcome resistance
- 68. Involvement of a transporters is more of a rule than an exception!!!!