Details of the Drug Combination

General Information of Drug Combination (ID: DC310V0)

• Drug Combination Name: Clindamycin + Clotrimazole
• Indication: Candidiasis; Status: Phase 4 [1]
• Component Drugs:
  Clindamycin (DM15HL8): Small molecular drug
  Clotrimazole (DMMFCIH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clindamycin

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[2]
Aspiration pneumonia	N.A.	Approved	[3]
Bacteremia	1A73	Approved	[3]
Bacterial vaginosis	MF3A	Approved	[3]
Pleural empyema	N.A.	Approved	[3]
Staphylococcal pneumonia	N.A.	Approved	[3]
Staphylococcus aureus infection	N.A.	Approved	[3]
Streptococcal pneumonia	N.A.	Approved	[3]
Pelvic inflammatory disease	GA05	Investigative	[3]

Clindamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 50S ribosomal RNA (Bact 50S rRNA)	TTUWYEA	NOUNIPROTAC	Binder	[6]

Clindamycin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Beta-lactamase (blaB)	DEMSNER	A4LA84_EDWTA	Metabolism	[8]

Clindamycin Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[9]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[10]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[10]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[11]

Indication(s) of Clotrimazole

Disease Entry	ICD 11	Status	REF
Cutaneous candidiasis	1F23.14	Approved	[4]
Fungal infection	1F29-1F2F	Approved	[5]
Mycoses	1F2Z	Approved	[4]
Oral candidiasis	1F23.0	Approved	[4]
Tinea corporis	1F28.Y	Approved	[4]
Tinea cruris	1F28.3	Approved	[4]
Tinea versicolor	1F2D.0	Approved	[4]
Tinea pedis	1F28.2	Investigative	[4]

Clotrimazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
C-X-C chemokine receptor type 2 (CXCR2)	TT30C9G	CXCR2_HUMAN	Modulator	[14]

Clotrimazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]

Clotrimazole Interacts with 37 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[17]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[17]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Expression	[18]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Expression	[19]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Activity	[20]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[21]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[22]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Expression	[23]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Activity	[24]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[25]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Affects Binding	[26]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[27]
Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4)	OTQKQ346	KCNN4_HUMAN	Decreases Activity	[28]
Adenylate cyclase type 9 (ADCY9)	OT1IZT5K	ADCY9_HUMAN	Decreases Activity	[29]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Expression	[30]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[30]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[30]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[31]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[32]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[33]
ATP-dependent 6-phosphofructokinase, muscle type (PFKM)	OT1QY9JM	PFKAM_HUMAN	Decreases Expression	[12]
Insulin-like growth factor-binding protein 1 (IGFBP1)	OT6UQV2K	IBP1_HUMAN	Increases Expression	[34]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[35]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[33]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Increases Expression	[30]
Cyclic AMP-dependent transcription factor ATF-3 (ATF3)	OTC1UOHP	ATF3_HUMAN	Increases Expression	[27]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Activity	[36]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[33]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[33]
Hexokinase-2 (HK2)	OTC0GCQO	HXK2_HUMAN	Decreases Expression	[12]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[37]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[38]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[31]
Eukaryotic translation initiation factor 2A (EIF2A)	OTWXELQP	EIF2A_HUMAN	Increases Phosphorylation	[39]
DnaJ homolog subfamily B member 4 (DNAJB4)	OTUD01BK	DNJB4_HUMAN	Increases Expression	[35]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[40]

References

• [1] ClinicalTrials.gov (NCT02860845) Use of Boric Acid in Combination With Probiotics for the Treatment of Vaginal Infections
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Clindamycin FDA Label
• [4] Clotrimazole FDA Label
• [5] 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: 2330).
• [6] Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001 Oct 25;413(6858):814-21.
• [7] In vitro metabolism of clindamycin in human liver and intestinal microsomes. Drug Metab Dispos. 2003 Jul;31(7):878-87.
• [8] Comparison of antimicrobial susceptibility, beta-lactamase production, plasmid analysis and serum bactericidal activity in Edwardsiella tarda, E. ictaluri and E. hoshinae. J Med Microbiol. 1993 Oct;39(4):273-81.
• [9] A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008 Aug;36(8):1689-97.
• [10] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [11] Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion. Toxicol Sci. 2010 Jul;116(1):140-50. doi: 10.1093/toxsci/kfq085. Epub 2010 Mar 25.
• [12] Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells. Chem Biol Interact. 2015 May 25;233:147-56. doi: 10.1016/j.cbi.2015.03.028. Epub 2015 Apr 8.
• [13] Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers. J Biochem Mol Toxicol. 2005;19(2):96-108. doi: 10.1002/jbt.20058.
• [14] Mode of action of clotrimazole: implications for therapy. Am J Obstet Gynecol. 1985 Aug 1;152(7 Pt 2):939-44.
• [15] Tacrolimus interaction with clotrimazole: a concise case report and literature review. P T. 2010 Oct;35(10):568-9.
• [16] Receptor-dependent regulation of the CYP3A4 gene. Toxicology. 2002 Dec 27;181-182:199-202.
• [17] Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996 Feb;49(2):311-8.
• [18] Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression. Toxicology. 2002 Feb 28;171(2-3):137-46.
• [19] Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003 Apr;26(4):510-7.
• [20] Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58.
• [21] Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans. Endocr Res. 2004 Aug;30(3):387-94.
• [22] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [23] Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression. Drug Metab Dispos. 2008 Feb;36(2):339-48.
• [24] Modulation of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) by 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives, ligands of peripheral benzodiazepine receptor (PBR). Toxicol Lett. 2011 Apr 25;202(2):148-54.
• [25] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [26] Different inhibitory effects of azole-containing drugs and pesticides on CYP2C9 polymorphic forms: an in vitro study. Toxicol In Vitro. 2018 Aug;50:249-256.
• [27] Activation of p38 Mitogen-Activated Protein Kinase by Clotrimazole Induces Multidrug Resistance-Associated Protein 3 Activation through a Novel Transcriptional Element. J Pharmacol Exp Ther. 2016 Oct;359(1):102-9. doi: 10.1124/jpet.115.231589. Epub 2016 Aug 9.
• [28] Functional and molecular identification of intermediate-conductance Ca(2+)-activated K(+) channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol. 2004 Jul;287(1):C125-34. doi: 10.1152/ajpcell.00488.2003. Epub 2004 Feb 25.
• [29] Direct stimulation of adenylyl cyclase 9 by the fungicide imidazole miconazole. Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):497-504. doi: 10.1007/s00210-018-01610-1. Epub 2019 Jan 3.
• [30] Effects of clotrimazole on the growth, morphological characteristics, and cisplatin sensitivity of human glioblastoma cells in vitro. J Neurosurg. 1999 May;90(5):918-27. doi: 10.3171/jns.1999.90.5.0918.
• [31] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [32] The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicology. 2019 Sep 1;425:152247. doi: 10.1016/j.tox.2019.152247. Epub 2019 Jul 19.
• [33] Clotrimazole induces a late G1 cell cycle arrest and sensitizes glioblastoma cells to radiation in vitro. Anticancer Drugs. 2010 Oct;21(9):841-9. doi: 10.1097/CAD.0b013e32833e8022.
• [34] Troglitazone stimulates IGF-binding protein-1 by a PPAR gamma-independent mechanism. Biochem Biophys Res Commun. 2003 Apr 4;303(2):693-9. doi: 10.1016/s0006-291x(03)00403-0.
• [35] An in vitro skin sensitization assay termed EpiSensA for broad sets of chemicals including lipophilic chemicals and pre/pro-haptens. Toxicol In Vitro. 2017 Apr;40:11-25. doi: 10.1016/j.tiv.2016.12.005. Epub 2016 Dec 10.
• [36] Improved assays for xenosensor activation based on reverse transfection. Toxicol In Vitro. 2015 Oct;29(7):1759-65. doi: 10.1016/j.tiv.2015.07.011. Epub 2015 Jul 14.
• [37] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [38] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [39] Androgen signaling promotes translation of TMEFF2 in prostate cancer cells via phosphorylation of the subunit of the translation initiation factor 2. PLoS One. 2013;8(2):e55257. doi: 10.1371/journal.pone.0055257. Epub 2013 Feb 6.
• [40] 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.