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

General Information of Drug (ID: DMPZI3Q)

• Drug Name: Ketoconazole Drug Info
• Synonyms: KCZ; KTZ; K 1003; R 41400; R41400; KS-1205; KW-1414; Perkhotal (TN); R 41,400; R-41400; R41,400; Ketoconazole [USAN:INN:BAN:JAN]; Nizoral, Extina, Xolegel, Kuric, Ketoconazole; Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-piperazine; Cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine; CIS-1-ACETYL-4-(4-((2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL)METHOXY)PHENYL)PIPERAZINE; (+-)-cis-1-Acetyl-4-(p-((2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine; (+/-)-cis-1-Acetyl-4-(4-[(2-[2,4-dichlorophenyl]-2-[1H-imidazol-1-ylmethyl]-1,3-dioxolan-4-yl)-methoxy]phenyl)piperazine; (+/-)-cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine; 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone; 1-acetyl-4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine

Indication

Disease Entry	ICD 11	Status	REF
Blastomycosis	1F22	Approved	[1]
Chromomycosis		Approved	[1]
Coccidioidomycosis	1F25	Approved	[1]
Cutaneous candidiasis	1F23.14	Approved	[1]
Fungal infection	1F29-1F2F	Approved	[2]
Histoplasmosis		Approved	[1]
Invasive candidiasis	1F23	Approved	[1]
Mycoses	1F2Z	Approved	[1]
Oral candidiasis	1F23.0	Approved	[1]
Paracoccidioidomycosis		Approved	[1]
Pityriasis simplex		Approved	[1]
Prostate adenocarcinoma		Approved	[1]
Tinea corporis	1F28.Y	Approved	[1]
Tinea cruris	1F28.3	Approved	[1]
Tinea versicolor	1F2D.0	Approved	[1]
Tinea pedis	1F28.2	Investigative	[1]

• Therapeutic Class: Antifungal Agents
• Cross-matching ID:
  PubChem CID: 456201
  ChEBI ID: CHEMBL48336
  CAS Number: CAS 65277-42-1
  TTD Drug ID: DMPZI3Q
  VARIDT Drug ID: DR00594
  INTEDE Drug ID: DR0906
  ACDINA Drug ID: D00342

Molecule-Related Drug Atlas

Drug(s) Targeting Candida Cytochrome P450 51 (Candi ERG11)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Voriconazole	DMAOL2S	Aspergillosis	1F20	Approved	[6]
Itraconazole	DMCR1MV	Aspergillosis	1F20	Approved	[6]
Posaconazole	DMUL5EW	Aspergillosis	1F20	Approved	[7]
Miconazole	DMPMYE8	Cutaneous candidiasis	1F23.14	Approved	[6]
Oxiconazole	DME7KRM	Tinea corporis	1F28.Y	Approved	[8]
Fluconazole	DMOWZ6B	Cryptococcal meningitis		Approved	[6]
Terconazole	DMJ13KI	Candidiasis	1F23	Approved	[9]
Bifonazole	DM3KN7V	Fungal infection	1F29-1F2F	Approved	[10]
Tioconazole	DMNYPGS	Onychomycosis	EE12.1	Approved	[11]
Econazole	DMFSWGH	Cutaneous candidiasis	1F23.14	Approved	[12]

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	[13]
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[14]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[4]
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[15]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[4]
Cisplatin	DMRHGI9	Adenocarcinoma	2D40	Approved	[4]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[16]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[4]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[17]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[18]

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	[19]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[20]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[21]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[22]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[23]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[24]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[25]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[26]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[20]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[27]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Inhibitor	[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]

References

• [1] Ketoconazole FDA Label
• [2] 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: 2568).
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• [5] The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole. J Pharm Pharm Sci. 2008;11(1):147-59.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [7] A new, broad-spectrum azole antifungal: posaconazole--mechanisms of action and resistance, spectrum of activity. Mycoses. 2006;49 Suppl 1:2-6.
• [8] Antifungal agents: mechanisms of action. Trends Microbiol. 2003 Jun;11(6):272-9.
• [9] Mode of action of anti-Candida drugs: focus on terconazole and other ergosterol biosynthesis inhibitors. Am J Obstet Gynecol. 1991 Oct;165(4 Pt 2):1193-9.
• [10] Investigation of the role of cytochrome P450 2B4 active site residues in substrate metabolism based on crystal structures of the ligand-bound enzyme. Arch Biochem Biophys. 2006 Nov 1;455(1):61-7.
• [11] Biological spectra analysis: Linking biological activity profiles to molecular structure. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):261-6.
• [12] Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homolo... Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603.
• [13] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [14] MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
• [15] Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
• [16] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
• [17] Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
• [18] 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.
• [19] 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.
• [20] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [21] 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.
• [22] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [23] 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.
• [24] 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.
• [25] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [26] 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.
• [27] 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.