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Drug transporters
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- 2. Introduction Typesof 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 comesto 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?
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- 7. Transport Ion Channels TransportersAquaporins
- 8. Aquaporins bi-directional membranechannels -transport water not ion channels- H2O is transported as an uncharged molecule driving force-osmotic gradient 13 AQP genes in the human genome
- 9. Transporters It formsan 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 s–1 Non saturable
- 11. 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
- 13. Physiological Role ofTransporters 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
- 15. 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
- 16. 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
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- 18. What does theterm ‘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.
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- 23. Following receptors formheterodimers with 9 cis- retinoic acid receptors Pregnane X receptor (PXR) Peroxisome proliferator activated receptor α (PPAR) Retinoic Acid Receptor (RAR) Farnesoind X Receptor (FXR)
- 24. Pregnane X Receptor Activatedby 1.Phenobarbitone 2.Rifampicin 3.Carbemezapine 4.Phenytoin
- 25. ATP Binding CassetteTransporter protein superfamily Transmembrane proteins utilize the energy of ATP hydrolysis 48 ABC genes in humans Can be divided into 7 groups
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- 27. Structure The commonstructure of all ABC – consists of 2 Distinct domains Transmembrane domain (TMD) Nucleotide binding Domain (NBD)
- 29. In mostExporters- 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
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- 33. GENE NAME FAMILY NAME NO. OF FAMILIES DIS. ASOCIATED ABCAABC 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
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- 39. SLC Transporters Includes48 families and represents 315 genes in human genome Contain hydrophobic transmembrane alpha helices Includes facilitative transporters and secondary active transporters
- 40. Nomenclature SLCnXm : SLC :root name n: family X: subfamily m: isoform
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- 44. Various transportersare 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
- 47. BCRP member ofthe 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
- 48. • BCRP Isexpressed also in the bile canalicular membrane and placenta • In pregnant GF120918 Treated P gp deficient mice,fetal penetration of topotecan was 2 fold higher
- 49. Oral drug inhibitortransporter Digoxin quinidine P gp Paclitaxel Cyclosporin P gp methotrexate Omeprazole BCRP irinotecan gefitinib BCRP
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- 54. Statins are substratefor uptake transporters • Uptake transporter- OATP1B1 • Efflux transporter- MRP2
- 55. Temocapril Temocaprilat- excretedin 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
- 56. IRINOTECAN CPT-11 SN-38 Glucuronide conjugation Excreted in bileby MRP-2 DIARRHOEA PROBENECID
- 57. Renal Transporters Renaltransporters play an important role in drug elimination ,toxicity and response Transporters may have dual specificity for organic anions and cations
- 59. Endogenous • Choline • Dopamine Exogenous •Cimetidine • Ranitidine • Metformin • procainamide
- 61. Organic Anion Transporters Weakacidic drugs like 1. Pravastatin 2. Captopril 3. Penicillin
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- 64. Role in CNS Involved in neuronal reuptake- SLC1 and SLC6 SLC6 responsible for reuptake of 1. norepinephrine 2. dopamine 3. serotonin 4. GABA
- 65. 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
- 66. Role of transportersin drug resistance
- 67. In 1976, Lingreported the overexpression of a membrane protein in colchicine resistance Chinese hamster ovary cells, acquired resistance to various other drugs!!
- 68. Q.1. What isthe genetic basis??? Q.2. How frequency will it occur?????
- 69. Hypothesis If a drug resistance occursat rate of 10-7 Resistance to 2 unrelated drugs 10 -14 Shouldnt that be very rare????
- 70.
- 71. • 170 kDatransmembrane 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
- 72. P gp inhumans MDR1 Responsible for efflux of drugs MDR2 Transport of phosphatidylcholine to bile
- 73. Epithelial cells : •Colon • intestine • Pancreas • Kidney • Adrenals Endothelial cells • brain
- 75. Models of actionof P gp
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- 79. 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
- 80. 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
- 81. Relation between Pgpand 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
- 82.
- 84. Transporters and drugresistance Play a critical role in developing resistance to Anti cancer Anti microbials Anti epileptics
- 85. Why resistance isso important to study? result in treatment failure increased costs, prolonged duration of hospital stay higher morbidity and mortality rates
- 86. How to overcome this resistance?
- 88. Approaches to overcomeMDR 1. REVERSAL AGENTS known as chemosensitisers inhibit P gp increase intracellular concentration of the drug
- 89. 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
- 90. 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
- 91. Third generation agents Agents were not substrates of CYP3A4 Selectively and potentially inhibit Pgp 1. Tariquidar XR9576 2. Zosuquidar LY335979 3. Laniquidar R101933
- 93. Newer ways toovercome 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
- 94. So why dowe need these transporters??? To regulate bioavailability To act as drug targets To eliminate toxins To overcome resistance
- 95. Involvement of atransporters is more of a rule than an exception!!!!
Editor's Notes
- #6 Passive diffusion-FQ Facilitated-beta lactams
- #7 Active aminoglycosides Symport-NA K 2CL Antiport- Na -H
- #17 Abc- unidirectional-efflux in eukaryotes
- #29 The TMD also known as Membrane Spanning Domain (MSD) OR Integral Domain (ID) consists of alpha helices embedded in lipid bilayer It recognises substrates and undergoes conformational change The sequence and architecture of TMD is variable, reflecting the chemical diversity of substrates that can be translocated The NBD is located in the cytoplasm Site for ATP binding
- #31 Exporters have an Intracellular domain (ICD) that joins the membrane spanning helices and ABC domain The ICD is believed to be responsible for communication between TMD and NBD
- #32 This model presents 2 principal conformation of the NBDs Formation of a A closed dimer on binding of the 2 ATP molecules Dissociation to an open dimer facilitated by the ATP hydrolysis Switching between the 2 conformations induces a conformational change in the TMD resulting in substrate translocation
- #33 Importers have a High Affinity Binding protein that specifically associates with the substrate in the periplasm The substrate binding site alternates between Outward and Inward facing conformation The relative binding affinities of the two conformations of the substrates determines the net direction of transport For importers- outward facing conformations have a higher binding affinity for the substrate Exporters - inward facing conformations have a higher binding affinity for the substrate
- #35 Abca1-
- #37 Defect in ABCC2 or MRP2
- #39 DEFECT IN abcc7- Acts as a broken leaky ABC TRANSPORTER
- #40 Located in the cell membrane
- #41 Only exception is SLC family 21: SLCO
- #45 PEPT-SLC15 Cefaplexin and not cefazolin P gp affects the absorption of many drugs because of its broad substrate specificity Intestinal P gp content correlates with the AUC after oral absorption of drugs like digoxin Eg. patient undergoing a small bowel transplant demonstrated that the plasma level of tacrolimus-a substrate for for both cyp 3A4 and P gp correlated more with the levels of P gp
- #48 Abcg2- It has only 1 ATP binding cassette- half transporter
- #53 NTCP- Hepatic uptake of anions, cations, bile salts is mediated by SLC Transporters in the basolateral membrane of hepatocytes OAT-transport of anions OCT and NCTP –transport cations and bile salts ABC Transporters like BSEP, MDR1, MRP2 In the bile canalicular membrane of hepatocytes mediates the efflux of drugs from liver to bile Ntcp-sodium taurocholate co trnsporter Imhibition of BSEP thru drugs lik troglitazone and rifampicin may lead to cholestasis
- #55 They together help In minimising the escape of these drugs into systemic circulation
- #56 Drugs that are excreted in both bile and urine to the same degree and thus are expected to have minimal interindividual variations in their pharmacokinetics
- #57 potent anticancer drug late-onset gastrointestinal toxic effects, such as severe diarrhoea
- #58 Secretion in the kidney is ritical in the body’s efence mechanisms against foreign substances
- #61 For the transepithelial flux of a compound, the compounds traverse 2 membranes OCT are Involved in the uptake of cations into liver or kidney from blood OCT1 and OCT2- epithelial cells of kidney, liver and intestines Located in the basolateral membrane Organic cations cross the basolateral membrane by 3 distinct transporters in the SLC family OCT1- SLC22A1 OCT2- SLC22A2 OCT3- SLC22A3 They are transported across this membrane down their electrochemical gradient Transport across the apical membrane occurs via proton organic cation exchange mechanism Transporters in the apical sde- novel org cations They r bifunctional..in d reuptake mode,they functn as sodium cotransporters relyng on inwardly driven Na gradient to move carnitine MATE-SLC47
- #63 Two primary transporters on basolateral membrane OAT1 (SLC22A6) OAT3 (SLC22A8
- #66 SLC6A/GAT1- most important GABA Transporter-presynaptic neurons antidepressant desipramine -selective inhibitor of NET In ADHD- methyphenidate-inhibits NET SLC6A11/GAT3- Target of anticonvulsants
- #82 In the case of fast absorbing drugs having larger doses, efflux by P-gp poses less impact on drug absorption the transport activity of P-gp becomes saturated by high concentrations of drug in the intestinal lumen. the case of drugs requiring a very small dose for their pharmacological actions or the drugs that have very slow dissolution and diffusion rates, P-gp mediated drug efflux greatly interferes with their delivery. As it decreases drug absorption, those small amounts of drugs cannot reach the blood circulation in sufficient quantity and, at times, can be life threatening. sustained release dosage forms of the substrates-ineffective
- #85 P gp is overexpressed in cancer cells Other transporters implicated in drug resistance are BCRP ( Breast Cancer Resistance protein) OAT (Organic Anion Transporter) MRP ( Multidrug reistance protein) Overexpression of MRP4 – Resistance to antiviral nucleoside analogues
- #86 Drug efflux-reduce intracellular drug concentrations
- #88 Altering memb permeability
- #93 Natural polymers Anionic gums : xanthan gum- P gp inhibitor at 0.05% From green tea- polyphenols From grapefruit juice- various polysaccharides like D- glucose thiomers- form disulphide bond between cysteine group of P gp and free thiol group of thiomer eg. α- chitosan-thiobutylamidine Liposomes They are vesicles made of bilayer- contain phospholipid and hydrophilic aqueous region Drug is encapsulated in this carrier Neutral PL are selectively pumped out- so competition for P-gp
- #94 ixabepilone
- #97 Lactose permease transporter-bacterial transporter that belongs to the major facilitator superfamily (MFS).