Details of the Drug Combination

General Information of Drug Combination (ID: DCKX0CV)

• Drug Combination Name: Rifabutin + Nevirapine
• Indication: HIV Infections; Status: Phase 4 [1]
• Component Drugs:
  Rifabutin (DM1YBHK): Small molecular drug
  Nevirapine (DM6HX9B): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Rifabutin

Disease Entry	ICD 11	Status	REF
Mycobacterium infection	1B10-1B21	Approved	[2]
Tuberculosis	1B10-1B14	Approved	[2]

Rifabutin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA-directed RNA polymerase (RNAP)	TTHKJLN	NOUNIPROTAC	Modulator	[4]

Rifabutin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[5]

Indication(s) of Nevirapine

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[3]

Nevirapine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[8]

Nevirapine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Nevirapine Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[12]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[13]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[14]

Nevirapine Interacts with 38 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Binding	[15]
Sterol carrier protein 2 (SCP2)	OTPAFCPQ	SCP2_HUMAN	Increases Expression	[16]
MHC class II transactivator (CIITA)	OTRJNZFO	C2TA_HUMAN	Increases Expression	[16]
Protein NLRC5 (NLRC5)	OTY8X6MC	NLRC5_HUMAN	Increases Expression	[16]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[17]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[6]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Decreases Expression	[6]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Increases Expression	[18]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[19]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[17]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Expression	[20]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[21]
Phosphatidylcholine-sterol acyltransferase (LCAT)	OTRLMLK0	LCAT_HUMAN	Increases Expression	[20]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[22]
Keratin, type I cytoskeletal 18 (KRT18)	OTVLQFIP	K1C18_HUMAN	Increases Expression	[6]
Lipoprotein lipase (LPL)	OTTW0267	LIPL_HUMAN	Increases Expression	[22]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Increases Expression	[18]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[6]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[17]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[17]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Expression	[6]
Cholesteryl ester transfer protein (CETP)	OTAGPPOE	CETP_HUMAN	Increases Expression	[20]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Decreases Secretion	[22]
Thyrotropin receptor (TSHR)	OT0BC8LB	TSHR_HUMAN	Increases Expression	[18]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[17]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Increases Expression	[22]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Expression	[22]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Increases Expression	[22]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[22]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Increases Expression	[17]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[17]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[22]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[17]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[17]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Increases Glutathionylation	[23]
Glutathione S-transferase A3 (GSTA3)	OTJ3REE3	GSTA3_HUMAN	Increases Glutathionylation	[23]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Increases Glutathionylation	[23]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Increases Glutathionylation	[23]

References

• [1] ClinicalTrials.gov (NCT02184078) Study to Determine the Effects of Nevirapine (VIRAMUNE) on the Steady State Pharmacokinetics of Rifabutin (MYCOBUTIN) in HIV+ Patients
• [2] Novel agents in the management of Mycobacterium tuberculosis disease. Curr Med Chem. 2007;14(18):2000-8.
• [3] Approved antiretroviral drugs. Antiretroviral Drugs. Company report of AVERT. 2009.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [5] The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin. Clin Pharmacol Ther. 1998 Apr;63(4):414-21.
• [6] Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo. Prostate. 2009 May 15;69(7):744-54. doi: 10.1002/pros.20923.
• [7] Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes. Antivir Ther. 2005;10(4):515-26.
• [8] HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism.Nat Struct Mol Biol.2012 Jan 22;19(2):253-9.
• [9] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [10] Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos. 1999 Dec;27(12):1488-95.
• [11] 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.
• [12] Helices F-G are important for the substrate specificities of CYP3A7. Drug Metab Dispos. 2007 Mar;35(3):484-92.
• [13] Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol. 2001 Jan;41(1):85-91.
• [14] RAT CYP3A and CYP2B1/2 were not associated with nevirapine-induced hepatotoxicity. Methods Find Exp Clin Pharmacol. 2006 Sep;28(7):423-31.
• [15] Bioactivation of nevirapine to a reactive quinone methide: implications for liver injury. Chem Res Toxicol. 2012 Aug 20;25(8):1708-19. doi: 10.1021/tx300172s. Epub 2012 Jul 26.
• [16] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [17] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [18] Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma. J Clin Endocrinol Metab. 2005 Oct;90(10):5663-71. doi: 10.1210/jc.2005-0367. Epub 2005 Jul 19.
• [19] Identification of danger signals in nevirapine-induced skin rash. Chem Res Toxicol. 2013 Sep 16;26(9):1378-83. doi: 10.1021/tx400232s. Epub 2013 Aug 30.
• [20] Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production. Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1336-41. doi: 10.1161/ATVBAHA.109.192088. Epub 2009 Aug 10.
• [21] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [22] Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res. 2011 Aug;91(2):112-9. doi: 10.1016/j.antiviral.2011.04.018. Epub 2011 May 17.
• [23] Different Reactive Metabolites of Nevirapine Require Distinct Glutathione S-Transferase Isoforms for Bioinactivation. Chem Res Toxicol. 2016 Dec 19;29(12):2136-2144. doi: 10.1021/acs.chemrestox.6b00250. Epub 2016 Nov 28.