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ABC. See ATP-Binding Cassette (ABC) ABC Transporters, 12, 107 325 Index a amidotransferases, 263 ABC. see ATP-binding cassette (ABC) – γ-glutamyl transpeptidase, 263 ABC transporters, 12, 107 amine hypothesis, 21 – effects on drug disposition, 112 amino acidpolyamine-organocation – mutations, 113 superfamily, 16 – neurological disorders, role in, 180–181 amino acid/polyamine/organocation – PET imaging, 181–183 transporter (APC), 262 – PET tracers amino acid transporters, 254 –– applications, 184–185 γ-aminobutyric acid (GABA), 24, 69 –– designing, challenges in, 184 – neurotransmission, 85 – pharmacochaperones and, 113, 114 – signaling, 73, 85 – proteins, 7 aminophospholipid, 204 – role of, 108 ammonia channel transporter (Amt) family, 7 – superfamily, 2 amyloid precursor protein (APP), 180 – from targets to antitargets, 111–113 anaesthetics, 1 absorption, disposition, metabolism and anion exchanger, 144 excretion (ADME), 253 anoctamin 1 (ANO1), 231, 233, 234 – SLC transporters, importance in, 253 – activators of, 240 acetylcholine, 41 – biophysical properties of, 234, 235 ADME. see absorption, disposition, metabolism – calcium activated chloride channel, 232 and excretion (ADME) – and cancer, 236–238 age-related insensitivity, 40 – characterization of, 232 alanine-serine-cysteine transporter 1 – as contributor to renal cyst growth, 245 (ASCT1), 260 – cystic fibrosis-related diabetes (CFRD), 232, alanine-serine-cysteine transporter 2 245 (ASCT2), 253, 260 – discovery of, 232, 233 Alisma orientalis, 212, 213 – effect on motility of human cancer cells, 237 allosteric effect – expression and physiological role of, 235, – citalopram, 29 236 – escitalopram, 28 – gene coding for, 236 allosteric mechanism, 30 – in GIST, 231 allosteric serotonin reuptake inhibitors – inhibition, during a type I asthma attack, 232 (ASRIs), 26 – inhibitors, structures of, 239 allosteric serotonin transporter – natural products, 240, 241 modulators, 28, 30 – as passenger event, 236 allosteric site, on serotonin transporter – pharmacological targeting of, 238 – localization of, 27, 28 – potential risks, of therapeutic – structure-activity relationships at, 28–30 intervention, 245, 246 alzheimer’s disease, 180 – small-molecule inhibitors of, 238–240 Transporters as Drug Targets, First Edition. Edited by Gerhard F. Ecker, Rasmus P. Clausen, and Harald H. Sitte. 2017 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2017 by Wiley-VCH Verlag GmbH & Co. KGaA. 326 Index – structure of, 234, 239 Atractylodes macrocephala, 212, 213 – therapeutic paradigms for, 246 attention deficit hyperactivity disorder – as therapeutic target, 241 (ADHD), 30 – for tumor growth in breast and head and neck audiogenic seizure (AGS), 86 cancers, 232 autoradiography, 40 anthranilic acid, 186, 187 antiarrhythmic drugs, 1 b anticancer drugs, 109, 131 BA homeostasis, 141 antidepressant, 22 BA-mediated activation, 202 – drug, 22, 24, 56 – of FXR, 201 –– nomenclature, 22–24 β-amyloid (Aβ) clearance, 180 – possible approach to a new classification BAs. see bile acids (BAs) of, 23 basolateral membrane, 199 – SNRIs, 32 basolateral transport proteins, 199 – therapies, 22 BBB. see blood-brain barrier (BBB) antidiabetic drug BCRP. see breast cancer resistance protein – metformin, 253 (BCRP) antiepileptic drug, 180 BCS. see Biopharmaceutics Classification antihypertensive drugs, 1 System (BCS) antineoplastic agents, 17 BDL. see bile duct ligated (BDL) antiporter, 5 benign recurrent intrahepatic cholestasis APC. see amino acid/polyamine/organocation (BRIC), 200 transporter (APC) benzimidazole derivatives, 218, 219 apical (canalicular) membrane, 199 betaine/GABA transporter 1 (BGT1), 74 approved drugs, and targeted transport BGT1. see betaine/GABA transporter 1 (BGT1) proteins, 14 bile acids (BAs), 113, 119, 201, 305 Aquifex aeolicus,55 – enterohepatic cycle, 199 N-arachidonyl-glycine (NAGly), 94 bile duct epithelium, 142 ASCT1. see alanine-serine-cysteine transporter bile duct ligated (BDL), 137 1 (ASCT1) bile salt export pump (BSEP or ABCB11), 121, ASCT2. see alanine-serine-cysteine transporter 200 2 (ASCT2) bilirubin, 126–128 asthma, 231, 242 – conjugated, 144 atherosclerosis, 135 – unconjugated, 129, 280, 285 atomoxetine, 30 bioactivity data counts, 15 ATPases, 7 Biopharmaceutics Classification System ATP-binding cassette (ABC), 179 (BCS), 111 – family, 5 BLAST search, 4 – proteins, 7, 10 blood-brain barrier (BBB), 112, 179, 263 – transporters, 119, 200 (see also ABC botulinum neurotoxin A, 12 transporters) brain –– basolateral, 119 – capillary endothelial cells, 179 ––ABCC3, 136 – pharmacological sanctuary, role as, 180 ––ABCC4, 138 breast cancer resistance protein (BCRP), –– canalicular, 119, 122 108 ––ABCB1, 126 breast cancers, 232 ––ABCB4, 131 Brintellix,38 ––ABCB11, 122 British Pharmacological Society (BPS), 5 ––ABCC2, 126 BSEP. see bile salt export pump (BSEP) ––ABCG2, 133 BSEP expression, mediated by CDCA, ––ABCG5/8, 131 203 ATP-dependent xenotoxin transport BSEP gene, 203 pump, 107 Byler disease, 204 Index 327 c ChEMBL classification, 2, 11 CA. see cholic acid (CA) – ChEMBL-16, 5, 7 Ca2+/calmodulin-dependent protein kinase –– transporter hierarchy, 5 IIα (αCaMKII), 58 – ChEMBL-18, 5 Caco-2 cell, 189 – ChEMBL-19, 12, 15 cafestol, 203 – database, 5 calcium channel blockers, 109 chemoconvulsants, 87 calmodulin, 235 chenodeoxycholic acid (CDCA), 121, 201 camptothecin, 189 chloride channel, 12 canalicular membrane, 202 chloride-independent transporters canalicular transport protein BSEP – leucine transporter (LeuT), 77 (ABCB11), 203 chloride (Cl ) ion, 231 cancer, 107, 231, 243–245 – channel activation, 231 cancer cells, 131 cholangiocytes, 207 cancer development cholehepatic shunt pathway, 207 – SLC transporters in, 263 cholestasis, 119, 200, 205 cancer metabolism – disorders, 201 – amino acid transporters in, 253 cholestasis of pregnancy (ICP), 123 – solute carriers in, 253–255 cholestatic diseases, 204 – targets, 260–263 cholestatic patients, 119 –– ASCT2, 260–262 – clinical management of, 145 –– LAT-1, 262–263 cholesterol, 201 cancer pathogenesis – lowering drug, 12 – SLC transporters, role in, 253 cholic acid (CA), 121 cancer-related transporters Cipralex ,26 – ASCT2, 264 cirrhosis, 113, 119, 130, 132, 210, 221, 298, 301 – LAT-1, 264 citalopram, 26–30, 38 cancer therapy, 15 c-Jun N-terminal kinase (JNK) pathways, 202 – transporter targeting in, 263 cladograms, 15 CAR. see constitutive androstane receptor classified membrane transport proteins in (CAR) IUPHAR/BPS, TCDB, and ChEMBL-16, CARM-1 (coactivator-associated arginine (“R”) overlap of, 11 methyl transferase-1), 207 clinical PET studies, 40 cation-chloride cotransporter (CCC) family clinical trials, 15, 82, 94, 95, 126, 140, 144, 221, (SLC 12), 1 240, 241, 243, 300 CDCA. see chenodeoxycholic acid (CDCA) clomipramine, 27, 56, 59 cell swelling, 125 cloxacillin, 203 central nervous system (CNS)-targeted Clustal Omega, 16 drugs, 180 cocrystallization, 78 cerebral ABC transporters cognitive dysfunction, 22 – PET tracers, 185–191 combined SERT inhibitors – –– radiolabelled BCRP substrates, 189 and 5-HT1A receptor antagonists, 37 –– radiolabelled dual P-gp/BCRP Commiphora mukul, 211 substrates, 189–190 conicasterol E, 213, 214 –– radiolabelled MRP1 substrates, 190–191 conjugated steroid metabolites, 204 –– radiolabelled P-gp inhibitors, 187–189 constipation, 15 –– radiolabelled P-gp substrates, 185–187 constitutive androstane receptor (CAR), 120, cerebrospinal fluid (CSF) biomarkers, 24 121, 125 CFRD. see cystic fibrosis-related diabetes contradictory classification in TCDB, IUPHAR/ (CFRD) BPS, and ChEMBL-16, 7, 8 CFTR. see cystic fibrosis transmembrane coumestrol, 214, 215 regulator (CFTR) cyclic adenosine monophosphate (cAMP), 231 channels of ChEMBL-16, 11 cyclosporine A, 203 328 Index Cymbalta,32 –– target–template alignment, 258 CYP7A1 expression, 219 –– template selection, 256–258 cystic fibrosis (CF), 113, 231, 241, 242 – virtual screening, 255 – caused by, 241 drug-induced alterations, 200 – mucus production, 232 drug-induced liver injury (DILI), 113 – treatment of, 242 drugs, pharmacokinetics of, 134 cystic fibrosis-related diabetes (CFRD), 245 drug targets, 69 cystic fibrosis transmembrane conductance – in SLC classification, 15 regulator (CFTR) protein, 12, 231 drug toxicity, 131 cytokines, 128, 129, 131, 138, 202, 232, 242 drug transporters, 131 cytosolic calcium, 234 – mutations in, 253 drug–transport interactions, 200 d Dubin–Johnson syndrome, 113, 127, 137, 200 Dalcipran,32 duloxetine, 25, 32, 35 DAT (dopamine transporter), 22 database database, 2 e 12-O-deacetyl-12-epi-19-deoxy-21- EBI Web server, 16 hydroxyscalarin, 213 edivoxetine (LY2216684), 30, 31 dendritic cells, 139 Effexor,32 Dendronephthya gigantean, 214 EGFR. see epidermal growth factor receptor’s depression, 21, 180 (EGFR) – and antidepressant drugs, disease biology endogenous modulator, 201 of, 24, 25 enterocytes, 205 desipramine, 28, 56 enterohepatic circulation, 202 diabetic nephropathy, 201 Enzyme Commission (EC) classification, 2 12,24-diacetoxy-deoxyscalarin, 213 epidermal growth factor receptor’s diarrhea, 212, 213, 231, 232, 236, 242, 243, 246 (EGFR), 190 dietary supplementation, 136 (-)-epigallocatechins-3-gallate (EGCG), 214, DILI. see drug-induced liver injury (DILI) 215 dimethoxytetrahydroisoquinolinylethyl, 186, Epilepsy, 85 187 – GABAergic system in, 85 discrete distribution, 24 – GAT role in, 86 DisGeNET, 15 epileptic brain tissue, 180 diterpene compound, 203 erlotinib, 180, 190 diuretics, 1, 14 ER-8 response element, 205 DNA-binding domain, 205 escitalopram, 25, 26 docking programs, 259, 260 – allosteric effect, 27 dopamine
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