Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMTW6IU)

Drug Name
Methadone Drug Info
Synonyms
Adanon; Algovetin; Althose; Amidon; Amidone; Biscuits; Dextromethadone; Diaminon; Dollies; Dolly; Dolophin; Dolophine; Heptadone; Heptanon; Ketalgin; Levometadona; Levomethadonum; Levothyl; Metadona; Metadone; Metasedin; Methadon; Methadona; Methadonum; Methaquaione; Phenadone; Polamidone; Polamivet; Westadone; Dolophine HCL; Levomethadone [INN]; Metadona [Spanish]; Metadone [DCIT]; Methadona [Spanish]; Methadone HCL Intensol; Methadone M; Methadonum [Latin]; Racemic methadone; A 4624; AN 148; Hoechst 10820; K 174; Amidone (TN); D-Methadone; Dl-Methadone; Dolophine (TN); Heptadon (TN); Heptanon (pharmaceutical); L-Methadone; L-Polamidon; L-Polamivet; Levometadona [INN-Spanish]; Levomethadonum [INN-Latin]; Metadona [INN-Spanish]; Methadone (BAN); Methadone [INN:BAN]; Methadonum [INN-Latin]; Methadose (TN); Physeptone (TN); Sedo-Rapide; Symoron (TN); Dolophine (*Hydrochloride*); Fenadone (*Hydrochloride*); Heptadone (*Hydrochloride*); Heptanon (*Hydrochloride*); Hoescht 10820 (*Hydrochloride*); Phenadone (*Hydrochloride*); AN-148 (*Hydrochloride*); L-(+)-Methadone; S-(+)-Methadone; D-6-(Dimethylamino)-4,4-diphenyl-3-heptanone; L-6-(Dimethylamino)-4,4-diphenyl-3-heptanone; (+)-Methadone; (+-)-Methadone; (+/-)-Methadone; (+/-)-Tussal; (-)-(R)-6-(Dimethylamino)-4,4-diphenyl-3-heptanone; (-)-Methadone; (6R)-Methadone; (R)-6-(Dimethylamino)-4,4-diphenyl-3-heptanone; (R)-6-(Dimethylamino)-4,4-diphenyl-3-hetpanone; (S)-6-(Dimethylamino)-4,4-diphenyl-3-heptanone; 3-Hetpanone, 6-(dimethylamino)-4,4-diphenyl-, (R)-(9CI); 6-(Dimethylamino)-4,4-diphenyl-3-heptanone dl-mixture; 6-(dimethylamino)-4,4-diphenylheptan-3-one; 6-Dimethylamino-4,4-diphenyl-3-heptanone; 6-dimethylamino-4,4-di(phenyl)heptan-3-one; 6S-Methadone
Indication
Disease Entry ICD 11 Status REF
Advanced cancer 2A00-2F9Z Approved [1]
Dry cough MD12 Approved [2]
Pain MG30-MG3Z Approved [1]
Therapeutic Class
Analgesics
Cross-matching ID
PubChem CID
4095
ChEBI ID
CHEMBL6807
CAS Number
CAS 76-99-3
TTD Drug ID
DMTW6IU
VARIDT Drug ID
DR00141
INTEDE Drug ID
DR1039
ACDINA Drug ID
D00406

Molecule-Related Drug Atlas

Molecule-Related Drug Atlas
Molecule Type:
DTT
DTP
DME
DOT
Drug Status:
Approved Drug(s)
Download the Complete Related Drug List
Drug(s) Targeting Opioid receptor (OPR)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Ketobemidone DMM3L6Z Pain MG30-MG3Z Approved [13]
Oxymorphone DM65AGJ Pain MG30-MG3Z Approved [14]
Dextropropoxyphene DM23HCX Pain MG30-MG3Z Approved [15]
Sufentanil DMU7YEL Analgesia MB40.8 Approved [16]
Naltrexone DMUL45H Alcohol dependence 6C40.2 Approved [17]
Levorphanol DMGS80V Pain MG30-MG3Z Approved [18]
Pentazocine DM1XBHS Pain MG30-MG3Z Approved [19]
Nalmefene DM4YWCZ Opioid dependence 6C43.2Z Approved [20]
Tilidine DMJW0VS Pain MG30-MG3Z Approved [21]
Dihydrocodeine DMB0FWL Allergic rhinitis CA08.0 Phase 4 [22]
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Drug(s) Transported By P-glycoprotein 1 (ABCB1)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Amoxicillin DMUYNEI Acute otitis media AB00 Approved [23]
Doxorubicin DMVP5YE Acute myelogenous leukaemia 2A41 Approved [24]
Methotrexate DM2TEOL Anterior urethra cancer Approved [25]
Folic Acid DMEMBJC Colorectal carcinoma Approved [26]
Fluorouracil DMUM7HZ Adenocarcinoma 2D40 Approved [25]
Cisplatin DMRHGI9 Adenocarcinoma 2D40 Approved [25]
Progesterone DMUY35B Amenorrhea GA20.0 Approved [27]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [25]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [28]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [29]
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Drug(s) Metabolized By Cytochrome P450 3A4 (CYP3A4)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Doxorubicin DMVP5YE Acute myelogenous leukaemia 2A41 Approved [30]
Progesterone DMUY35B Amenorrhea GA20.0 Approved [31]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [32]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [33]
Acetaminophen DMUIE76 Allergic rhinitis CA08.0 Approved [34]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [35]
Etoposide DMNH3PG Acute myelogenous leukaemia 2A41 Approved [36]
Zidovudine DM4KI7O Human immunodeficiency virus infection 1C62 Approved [37]
Prasterone DM67VKL Chronic obstructive pulmonary disease CA22 Approved [31]
Verapamil DMA7PEW Angina pectoris BA40 Approved [38]
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Drug(s) Metabolized By Aromatase (CYP19A1)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Prasterone DM67VKL Chronic obstructive pulmonary disease CA22 Approved [39]
Letrozole DMH07Y3 Estrogen-receptor positive breast cancer Approved [40]
Nandrolone DMFWKG1 Osteoporosis FB83.0 Approved [41]
Levomethadyl acetate hydrochloride DM429AE N. A. N. A. Approved [42]
Testosterone cypionate DMC1TEV N. A. N. A. Approved [43]
Dihydrotestosterone DM3S8XC Prostate hyperplasia GA90 Phase 4 [44]
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Drug(s) Metabolized By Cytochrome P450 1A2 (CYP1A2)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Fluorouracil DMUM7HZ Adenocarcinoma 2D40 Approved [45]
Dinoprostone DMTYOPD Medical abortion JA00.1Z Approved [46]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [47]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [48]
Acetaminophen DMUIE76 Allergic rhinitis CA08.0 Approved [49]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [50]
Etoposide DMNH3PG Acute myelogenous leukaemia 2A41 Approved [36]
Oxaliplatin DMQNWRD Adenocarcinoma 2D40 Approved [51]
Verapamil DMA7PEW Angina pectoris BA40 Approved [52]
Diclofenac DMPIHLS Chronic renal failure GB61.Z Approved [53]
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Drug(s) Metabolized By Cytochrome P450 2D6 (CYP2D6)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Doxorubicin DMVP5YE Acute myelogenous leukaemia 2A41 Approved [54]
Progesterone DMUY35B Amenorrhea GA20.0 Approved [55]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [56]
Acetaminophen DMUIE76 Allergic rhinitis CA08.0 Approved [34]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [38]
Quinine DMSWYF5 Malaria 1F40-1F45 Approved [57]
Propofol DMB4OLE Anaesthesia 9A78.6 Approved [58]
Dopamine DMPGUCF Acromegaly 5A60.0 Approved [59]
Nicotine DMWX5CO Lung cancer 2C25.0 Approved [60]
Propranolol DM79NTF Angina pectoris BA40 Approved [61]
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Drug(s) Metabolized By Cytochrome P450 3A7 (CYP3A7)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Progesterone DMUY35B Amenorrhea GA20.0 Approved [62]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [63]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [63]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [63]
Prasterone DM67VKL Chronic obstructive pulmonary disease CA22 Approved [64]
Verapamil DMA7PEW Angina pectoris BA40 Approved [65]
Sorafenib DMS8IFC Adenocarcinoma 2D40 Approved [63]
Quinine DMSWYF5 Malaria 1F40-1F45 Approved [63]
Irinotecan DMP6SC2 Adenocarcinoma 2D40 Approved [63]
Metronidazole DMTIVEN Abscess Approved [66]
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Drug(s) Metabolized By Cytochrome P450 2C18 (CYP2C18)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Verapamil DMA7PEW Angina pectoris BA40 Approved [64]
Diclofenac DMPIHLS Chronic renal failure GB61.Z Approved [67]
Propofol DMB4OLE Anaesthesia 9A78.6 Approved [68]
Phenytoin DMNOKBV Epilepsy 8A60-8A68 Approved [64]
Tretinoin DM49DUI Acne vulgaris ED80 Approved [69]
Diazepam DM08E9O Alcohol withdrawal Approved [70]
Dapsone DM4LT8A Acne vulgaris ED80 Approved [71]
Lidocaine DML4ZOT Anaesthesia 9A78.6 Approved [64]
Phenobarbital DMXZOCG Cluster headache 8A81.0 Approved [72]
Ifosfamide DMCT3I8 Adult central nervous system germ cell tumor Approved [73]
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Drug(s) Metabolized By Cytochrome P450 2C8 (CYP2C8)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Fluorouracil DMUM7HZ Adenocarcinoma 2D40 Approved [45]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [74]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [74]
Zidovudine DM4KI7O Human immunodeficiency virus infection 1C62 Approved [64]
Verapamil DMA7PEW Angina pectoris BA40 Approved [75]
Diclofenac DMPIHLS Chronic renal failure GB61.Z Approved [76]
Sorafenib DMS8IFC Adenocarcinoma 2D40 Approved [77]
Quinine DMSWYF5 Malaria 1F40-1F45 Approved [74]
Mycophenolate mofetil DMPQAGE Hepatosplenic T-cell lymphoma Approved [78]
Propofol DMB4OLE Anaesthesia 9A78.6 Approved [68]
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Drug(s) Metabolized By Cytochrome P450 2C9 (CYP2C9)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Progesterone DMUY35B Amenorrhea GA20.0 Approved [79]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [80]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [81]
Acetaminophen DMUIE76 Allergic rhinitis CA08.0 Approved [64]
Imatinib DM7RJXL Acute lymphoblastic leukaemia 2A85 Approved [82]
Zidovudine DM4KI7O Human immunodeficiency virus infection 1C62 Approved [64]
Verapamil DMA7PEW Angina pectoris BA40 Approved [83]
Diclofenac DMPIHLS Chronic renal failure GB61.Z Approved [84]
Estrone DM5T6US Acne vulgaris ED80 Approved [85]
Valproate DMCFE9I Epilepsy 8A60-8A68 Approved [86]
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Drug(s) Metabolized By Cytochrome P450 2B6 (CYP2B6)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [87]
Verapamil DMA7PEW Angina pectoris BA40 Approved [64]
Diclofenac DMPIHLS Chronic renal failure GB61.Z Approved [88]
Estrone DM5T6US Acne vulgaris ED80 Approved [81]
Valproate DMCFE9I Epilepsy 8A60-8A68 Approved [89]
Irinotecan DMP6SC2 Adenocarcinoma 2D40 Approved [90]
Propofol DMB4OLE Anaesthesia 9A78.6 Approved [91]
Nicotine DMWX5CO Lung cancer 2C25.0 Approved [92]
Phenytoin DMNOKBV Epilepsy 8A60-8A68 Approved [93]
Amitriptyline DMK7F9S Depression 6A70-6A7Z Approved [94]
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Drug(s) Metabolized By Mephenytoin 4-hydroxylase (CYP2C19)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Amoxicillin DMUYNEI Acute otitis media AB00 Approved [95]
Progesterone DMUY35B Amenorrhea GA20.0 Approved [79]
Tamoxifen DMLB0EZ Breast cancer 2C60-2C65 Approved [96]
Estradiol DMUNTE3 Acne vulgaris ED80 Approved [97]
Zidovudine DM4KI7O Human immunodeficiency virus infection 1C62 Approved [64]
Verapamil DMA7PEW Angina pectoris BA40 Approved [98]
Diclofenac DMPIHLS Chronic renal failure GB61.Z Approved [67]
Valproate DMCFE9I Epilepsy 8A60-8A68 Approved [86]
Quinine DMSWYF5 Malaria 1F40-1F45 Approved [99]
Propofol DMB4OLE Anaesthesia 9A78.6 Approved [68]
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Drug(s) Affected By ATP-dependent translocase ABCB1 (ABCB1)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Flupentixol DM0DJ9O Schizophrenia 6A20 Approved [100]
Sertraline DM0FB1J Coronary heart disease BA80.Z Approved [101]
Crizotinib DM4F29C Non-small-cell lung cancer 2C25.Y Approved [102]
Lamotrigine DM8SXYG Bipolar disorder 6A60 Approved [103]
Cepharanthine DM9Y5JB N. A. N. A. Approved [104]
Itraconazole DMCR1MV Aspergillosis 1F20 Approved [105]
Clozapine DMFC71L Schizophrenia 6A20 Approved [106]
Midostaurin DMI6E0R Acute myeloid leukaemia 2A60 Approved [107]
Trifluoperazine DMKBYWI Anxiety Approved [108]
Olanzapine DMPFN6Y Bipolar depression Approved [106]
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Drug(s) Affected By Alpha-1-acid glycoprotein 2 (ORM2)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Imipramine DM2NUH3 Depression 6A70-6A7Z Approved [9]
Quercetin DM3NC4M Obesity 5B81 Approved [109]
Tretinoin DM49DUI Acne vulgaris ED80 Approved [110]
Panobinostat DM58WKG Chronic graft versus host disease Approved [111]
Disopyramide DM5SYZP Long QT syndrome BC65.0 Approved [9]
Chlorpromazine DMBGZI3 Acute intermittent hepatic porphyria 5C58.11 Approved [9]
Testosterone DM7HUNW Hot flushes GA30 Approved [112]
Calcitriol DM8ZVJ7 Congenital alopecia LC30 Approved [112]
Ciclosporin DMAZJFX Graft-versus-host disease 4B24 Approved [113]
Valproate DMCFE9I Epilepsy 8A60-8A68 Approved [114]
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Drug(s) Affected By Mitogen-activated protein kinase 3 (MAPK3)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Cisplatin DMRHGI9 Adenocarcinoma 2D40 Approved [115]
Progesterone DMUY35B Amenorrhea GA20.0 Approved [116]
Cannabidiol DM0659E Dravet syndrome 8A61.11 Approved [117]
Sertraline DM0FB1J Coronary heart disease BA80.Z Approved [118]
Beta-carotene DM0RXBT Vitamin deficiency 5B55-5B71 Approved [119]
Fulvestrant DM0YZC6 Breast cancer 2C60-2C65 Approved [120]
Secobarbital DM14RF5 Epilepsy 8A60-8A68 Approved [121]
Gefitinib DM15F0X Colon adenocarcinoma Approved [122]
Fexofenadine DM17ONX Allergic rhinitis CA08.0 Approved [123]
Hydrogen peroxide DM1NG5W Infectious disease 1A00-CA43.1 Approved [124]
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Drug(s) Affected By Mitogen-activated protein kinase 1 (MAPK1)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Ethanol DMDRQZU Chronic pain MG30 Approved [125]
Progesterone DMUY35B Amenorrhea GA20.0 Approved [116]
Carvedilol DMHTEAO Chronic heart failure BD1Z Approved [126]
Paclitaxel DMLB81S Breast carcinoma Approved [127]
Etoposide DMNH3PG Acute myelogenous leukaemia 2A41 Approved [128]
Cisplatin DMRHGI9 Adenocarcinoma 2D40 Approved [115]
Urokinase DM0GOUD Myocardial infarction BA41-BA43 Approved [129]
Cannabidiol DM0659E Dravet syndrome 8A61.11 Approved [130]
Sertraline DM0FB1J Coronary heart disease BA80.Z Approved [118]
Beta-carotene DM0RXBT Vitamin deficiency 5B55-5B71 Approved [119]
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Drug(s) Affected By Cytochrome c (CYCS)
Drug Name Drug ID Indication ICD 11 Highest Status REF
Cannabidiol DM0659E Dravet syndrome 8A61.11 Approved [130]
Fulvestrant DM0YZC6 Breast cancer 2C60-2C65 Approved [131]
Gefitinib DM15F0X Colon adenocarcinoma Approved [132]
Leuprorelin acetate DM15HAT Prostate cancer 2C82.0 Approved [133]
Hydrogen peroxide DM1NG5W Infectious disease 1A00-CA43.1 Approved [134]
Nitric Oxide DM1RBYG Hypertension BA00-BA04 Approved [135]
Methotrexate DM2TEOL Anterior urethra cancer Approved [136]
Quercetin DM3NC4M Obesity 5B81 Approved [109]
Troglitazone DM3VFPD Diabetic complication 5A2Y Approved [137]
Pefloxacin DM49IGF Gonococcal urethritis 1A70.0Y Approved [138]
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Molecular Interaction Atlas of This Drug

Molecular Interaction Atlas
Download the Complete Interaction Atlas for Visualization in Cytoscape

Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Opioid receptor (OPR) TTN4QDT NOUNIPROTAC Agonist [3]

Drug Transporter (DTP)
DTP Name DTP ID UniProt ID MOA REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [4]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
Cytochrome P450 3A4 (CYP3A4) Main DME DE4LYSA CP3A4_HUMAN Substrate [5]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Substrate [5]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Substrate [5]
Mephenytoin 4-hydroxylase (CYP2C19) Main DME DEGTFWK CP2CJ_HUMAN Substrate [5]
Cytochrome P450 1A2 (CYP1A2) DEJGDUW CP1A2_HUMAN Substrate [6]
Aromatase (CYP19A1) DEQX145 CP19A_HUMAN Substrate [7]
Cytochrome P450 2B6 (CYP2B6) Main DME DEPKLMQ CP2B6_HUMAN Substrate [5]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Substrate [5]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Substrate [5]
Cytochrome P450 2C18 (CYP2C18) DEZMWRE CP2CI_HUMAN Substrate [8]

Drug Off-Target (DOT)
DOT Name DOT ID UniProt ID Interaction REF
Alpha-1-acid glycoprotein 2 (ORM2) OTRJGZP8 A1AG2_HUMAN Protein Interaction/Cellular Processes [9]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Gene/Protein Processing [10]
Cytochrome c (CYCS) OTBFALJD CYC_HUMAN Protein Interaction/Cellular Processes [11]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Post-Translational Modifications [12]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Post-Translational Modifications [12]

References

1 Methadone FDA Label
2 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
3 Methadone treatment and its dangers. Medicina (Kaunas). 2009;45(5):419-25.
4 In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R,S)-methadone, LAAM and their main metabolites. Pharmacology. 2007;80(4):304-11.
5 Methadone metabolism and drug-drug interactions: in vitro and in vivo literature review. J Pharm Sci. 2018 Dec;107(12):2983-2991.
6 Methadone--metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004 Dec;50(6):551-9.
7 Bidirectional transfer of methadone across human placenta. Biochem Pharmacol. 2005 Jan 1;69(1):187-97.
8 Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol. 1996 Mar;9(2):365-73.
9 Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
10 Comparative effects of drugs on P-glycoprotein expression and activity using rat and human trophoblast models. Toxicol In Vitro. 2010 Mar;24(2):630-7. doi: 10.1016/j.tiv.2009.10.005. Epub 2009 Oct 17.
11 Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis. Biochim Biophys Acta. 2010 Nov;1802(11):1036-47. doi: 10.1016/j.bbadis.2010.07.024. Epub 2010 Aug 3.
12 opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol. 2013 Oct 15;263(1-2):35-42. doi: 10.1016/j.jneuroim.2013.07.012. Epub 2013 Jul 25.
13 The mu1 and mu2 opioid receptor binding of ketobemidone, norketobemidone and 3-dimethylamino-1,1-diphenylbutene. Pharmacol Toxicol. 1996 Aug;79(2):103-4.
14 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7094).
15 Retrospective diagnosis of an adverse drug reaction in a breastfed neonate: liquid chromatography-tandem mass spectrometry quantification of dextropropoxyphene and norpropoxyphene in newborn and maternal hair. J Anal Toxicol. 2008 Nov-Dec;39(9):787-9.
16 mu-opioid receptor-stimulated synthesis of reactive oxygen species is mediated via phospholipase D2. J Neurochem. 2009 Aug;110(4):1288-96.
17 An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008 Feb;65(2):135-44.
18 Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis. J Pharmacol Exp Ther. 2004 May;309(2):515-22.
19 Functional characterization of a sigma receptor and its gene expression by haloperidol. Nippon Yakurigaku Zasshi. 1999 Jul;114(1):61-8.
20 Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospin... J Pharmacol Exp Ther. 2009 Feb;328(2):588-97.
21 Actions of tilidine and nortilidine on cloned opioid receptors. Eur J Pharmacol. 2005 Jan 4;506(3):205-8.
22 Affinities of dihydrocodeine and its metabolites to opioid receptors. Pharmacol Toxicol. 2002 Aug;91(2):57-63.
23 Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
24 MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
25 Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
26 Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
27 Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
28 Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
29 Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011 Apr;33(2):244-50.
30 Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
31 Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
32 Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
33 Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
34 Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
35 Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
36 Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
37 The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
38 Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
39 Urinary and serum octopamine in patients with portal-systemic encephalopathy. Lancet. 1975 Nov 15;2(7942):943-6.
40 Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
41 Aromatization of testosterone and 19-nortestosterone by a single enzyme from equine testicular microsomes. Differences from human placental aromatase. J Steroid Biochem. 1988 Jan;29(1):119-25.
42 N-demethylation of levo-alpha-acetylmethadol by human placental aromatase. Biochem Pharmacol. 2004 Mar 1;67(5):885-92.
43 Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease? Brain Res Rev. 2008 Mar;57(2):431-43.
44 Identifying susceptibility genes for prostate cancer--a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):2035-9.
45 Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
46 Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
47 Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
48 Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
49 PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
50 The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
51 The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
52 Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
53 Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
54 Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
55 Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
56 CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
57 Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
58 Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
59 Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
60 Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
61 Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
62 The role of cytochrome P450 3A (CYP3A) isoform(s) in oxidative metabolism of testosterone and benzphetamine in human adult and fetal liver. J Steroid Biochem Mol Biol. 1993 Jan;44(1):61-7.
63 Drug Interactions Flockhart Table
64 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
65 Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos. 2004 Feb;32(2):259-66.
66 The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
67 Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
68 Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
69 Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol. 2000 Dec;58(6):1341-8.
70 Targeted antipeptide antibodies to cytochrome P450 2C18 based on epitope mapping of an inhibitory monoclonal antibody to P450 2C51. Arch Biochem Biophys. 1997 Feb 15;338(2):157-64.
71 CYP2C8/9 mediate dapsone N-hydroxylation at clinical concentrations of dapsone. Drug Metab Dispos. 2000 Aug;28(8):865-8.
72 Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos. 2001 Mar;29(3):242-51.
73 Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos. 1999 Jun;27(6):655-66.
74 Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
75 Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003 Sep;13(9):565-75.
76 Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry. 2004 Dec 14;43(49):15379-92.
77 Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8.
78 PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
79 Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
80 Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
81 Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
82 Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
83 Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
84 New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
85 A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
86 A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
87 Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
88 Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol. 1999 Sep 1;58(5):787-96.
89 Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
90 Drugs that may have potential CYP2B6 interactions.
91 Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 Jul;37(7):717-24.
92 Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone metabolism by cytochrome P450 2B6. Drug Metab Dispos. 2005 Dec;33(12):1760-4.
93 PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70.
94 Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes: studies on amitriptyline as a model substrate. J Pharmacol Exp Ther. 2001 Apr;297(1):326-37.
95 High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
96 Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
97 CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
98 Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
99 Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
100 Characteristics of P388/VMDRC.04, a simple, sensitive model for studying P-glycoprotein antagonists. Cancer Res. 1994 Feb 1;54(3):730-7.
101 Michaelis-Menten kinetic analysis of drugs of abuse to estimate their affinity to human P-glycoprotein. Toxicol Lett. 2013 Feb 27;217(2):137-42. doi: 10.1016/j.toxlet.2012.12.012. Epub 2012 Dec 27.
102 Editor's Highlight: PlacentalDisposition and Effects of Crizotinib: An Ex Vivo Study in the Isolated Dual-Side Perfused Human Cotyledon. Toxicol Sci. 2017 Jun 1;157(2):500-509. doi: 10.1093/toxsci/kfx063.
103 Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. Pharmacogenet Genomics. 2008 May;18(5):390-402. doi: 10.1097/FPC.0b013e3282f85e36.
104 Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells. Cancer Sci. 2005 Jun;96(6):372-6. doi: 10.1111/j.1349-7006.2005.00057.x.
105 Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. Ther Drug Monit. 2005 Jun;27(3):322-33. doi: 10.1097/01.ftd.0000150135.22645.ea.
106 Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein. Psychopharmacology (Berl). 2006 Sep;187(4):415-23. doi: 10.1007/s00213-006-0437-9. Epub 2006 Jun 30.
107 Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002 Feb;87(2):167-76.
108 Characterization of the ATPase activity of the Mr 170,000 to 180,000 membrane glycoprotein (P-glycoprotein) associated with multidrug resistance in K562/ADM cells. Cancer Res. 1988 Sep 1;48(17):4926-32.
109 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
110 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
111 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
112 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
113 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
114 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
115 Treatment with anticancer agents induces dysregulation of specific Wnt signaling pathways in human ovarian luteinized granulosa cells in vitro. Toxicol Sci. 2013 Nov;136(1):183-92. doi: 10.1093/toxsci/kft175. Epub 2013 Aug 16.
116 Progesterone increases csk homologous kinase in HMC-1560 human mast cells and reduces cell proliferation. J Cell Biochem. 2007 Dec 1;102(5):1271-80. doi: 10.1002/jcb.21357.
117 Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact. 2017 Aug 1;273:107-114. doi: 10.1016/j.cbi.2017.06.005. Epub 2017 Jun 7.
118 Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway. Toxicol Sci. 2014 Feb;137(2):404-15. doi: 10.1093/toxsci/kft254. Epub 2013 Nov 5.
119 Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2. Int J Cancer. 2006 Mar 15;118(6):1370-80. doi: 10.1002/ijc.21537.
120 Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell-matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis. Toxicol Appl Pharmacol. 2014 Mar 1;275(2):176-81. doi: 10.1016/j.taap.2014.01.005. Epub 2014 Jan 17.
121 Inhibition of activator protein 1 by barbiturates is mediated by differential effects on mitogen-activated protein kinases and the small G proteins ras and rac-1. J Pharmacol Exp Ther. 2004 Dec;311(3):1232-40. doi: 10.1124/jpet.104.071332. Epub 2004 Jul 19.
122 Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance. Breast Cancer Res Treat. 2010 Feb;119(3):575-91. doi: 10.1007/s10549-009-0355-8. Epub 2009 Mar 15.
123 Effect of histamine H1 receptor antagonists on TARC/CCL17 and MDC/CCL22 production from CD14+ cells induced by antigenic stimulation in vitro. Int Arch Allergy Immunol. 2011;155(1):38-51. doi: 10.1159/000318720. Epub 2010 Nov 25.
124 SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells. Antioxid Redox Signal. 2016 Feb 20;24(6):329-43. doi: 10.1089/ars.2015.6331. Epub 2015 Nov 10.
125 Downregulation of mitogen-activated protein kinases (MAPKs) in chronic ethanol-induced fatty liver. Toxicol Mech Methods. 2020 Jul;30(6):407-416. doi: 10.1080/15376516.2020.1747126. Epub 2020 Apr 1.
126 A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. doi: 10.1073/pnas.0707936104. Epub 2007 Oct 9.
127 The stent-eluting drugs sirolimus and paclitaxel suppress healing of the endothelium by induction of autophagy. Am J Pathol. 2009 Nov;175(5):2226-34.
128 Modulation of apoptosis in HaCaT keratinocytes via differential regulation of ERK signaling pathway by flavonoids. J Biol Chem. 2005 Sep 9;280(36):31498-507. doi: 10.1074/jbc.M505537200. Epub 2005 Jul 13.
129 ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
130 Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
131 Regulation of ERRalpha gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: differential molecular mechanisms mediated by g protein-coupled receptor GPR30/GPER-1. Mol Endocrinol. 2010 May;24(5):969-80. doi: 10.1210/me.2009-0148. Epub 2010 Mar 8.
132 Evidence of securin-mediated resistance to gefitinib-induced apoptosis in human cancer cells. Chem Biol Interact. 2013 Apr 25;203(2):412-22. doi: 10.1016/j.cbi.2013.03.011. Epub 2013 Mar 22.
133 Effects of gonadotrophin-releasing hormone agonists on apoptosis of granulosa cells. Ann N Y Acad Sci. 2005 May;1042:531-7. doi: 10.1196/annals.1338.065.
134 K-RAS transformation in prostate epithelial cell overcomes H2O2-induced apoptosis via upregulation of gamma-glutamyltransferase-2. Toxicol In Vitro. 2012 Apr;26(3):429-34. doi: 10.1016/j.tiv.2012.01.013. Epub 2012 Jan 17.
135 Nitric oxide inhibits execution of apoptosis at two distinct ATP-dependent steps upstream and downstream of mitochondrial cytochrome c release. Biochem Biophys Res Commun. 1999 Apr 29;258(1):215-21. doi: 10.1006/bbrc.1999.0491.
136 The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
137 Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor co-activator-1 protein. Br J Pharmacol. 2010 Oct;161(4):771-81. doi: 10.1111/j.1476-5381.2010.00900.x.
138 Under ambient UVA exposure, pefloxacin exhibits both immunomodulatory and genotoxic effects via multiple mechanisms. J Photochem Photobiol B. 2018 Jan;178:593-605. doi: 10.1016/j.jphotobiol.2017.12.014. Epub 2017 Dec 15.