Details of the Drug Combination

General Information of Drug Combination (ID: DC13ZKW)

• Drug Combination Name: Lopinavir + Buprenorphine
• Indication: HIV Infections; Status: Phase 1 [1]
• Component Drugs:
  Lopinavir (DMITQS0): Small molecular drug
  Buprenorphine (DMPRI8G): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lopinavir

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[3]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[3]

Lopinavir Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 23S ribosomal RNA (Bact 23S rRNA)	TTLFGBV	NOUNIPROTAC	Modulator	[9]
MERS-CoV 3C-like proteinase (3CLpro)	TTWOH4Q	R1AB_CVEMC (3248-3553)	Inhibitor	[3]
SARS-CoV 3C-like protease (3CLpro)	TTPZG3C	R1AB_CVHSA (3241-3546)	Inhibitor	[3]

Lopinavir Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[11]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[13]

Lopinavir Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]

Lopinavir Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[15]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Abundance	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[17]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[18]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[18]
Prelamin-A/C (LMNA)	OT3SG7ZR	LMNA_HUMAN	Increases Farnesylation	[8]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[18]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[19]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Affects Phosphorylation	[20]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[19]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[18]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[18]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[18]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[18]

Indication(s) of Buprenorphine

Disease Entry	ICD 11	Status	REF
Opioid dependence	6C43.2Z	Approved	[4]
Pain	MG30-MG3Z	Approved	[5]
Psychiatric disorder	6E8Z	Phase 3	[6]
Migraine	8A80	Phase 2	[7]
Chronic pain	MG30	Investigative	[4]

Buprenorphine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Agonist	[22]

Buprenorphine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[23]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[24]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[25]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[26]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[27]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[28]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[29]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]

Buprenorphine Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[30]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[30]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Expression	[31]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[31]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[31]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[31]

References

• [1] ClinicalTrials.gov (NCT00571961) Pharmacokinetic Interactions Between Buprenorphine and Kaletra (Lopinavir/Ritonavir)
• [2] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [3] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [4] Buprenorphine 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: 1670).
• [6] ClinicalTrials.gov (NCT02510014) Safety and Tolerability Study of Depot Buprenorphine in Treatment Seeking Subjects With Opioid Use Disorder.
• [7] ClinicalTrials.gov (NCT00941304) Study of BEMA Buprenorphine in the Treatment of Dental Pain. U.S. National Institutes of Health.
• [8] A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells. J Biol Chem. 2008 Apr 11;283(15):9797-804. doi: 10.1074/jbc.M709629200. Epub 2008 Jan 28.
• [9] Company report (JMI Laboratories)
• [10] Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother. 2007 Nov;60(5):987-93.
• [11] Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol. 2010 Jul;160(5):1224-33.
• [12] 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.
• [13] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [14] Synthesis and antiviral activities of the major metabolites of the HIV protease inhibitor ABT-378 (Lopinavir). Bioorg Med Chem Lett. 2001 Jun 4;11(11):1351-3.
• [15] Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther. 2005 Feb;312(2):583-91.
• [16] Functional defect caused by the 4544G>A SNP in ABCC2: potential impact for drug cellular disposition. Pharmacogenet Genomics. 2011 Dec;21(12):884-93. doi: 10.1097/FPC.0b013e32834d672b.
• [17] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [18] Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
• [19] Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction. Free Radic Biol Med. 2016 May;94:218-29. doi: 10.1016/j.freeradbiomed.2016.03.003. Epub 2016 Mar 8.
• [20] Lopinavir inhibits meningioma cell proliferation by Akt independent mechanism. J Neurooncol. 2011 Feb;101(3):441-8. doi: 10.1007/s11060-010-0281-y. Epub 2010 Jul 2.
• [21] The effect of incubation conditions on the enzyme kinetics of udp-glucuronosyltransferases. Drug Metab Dispos. 2003 Jun;31(6):762-7. doi: 10.1124/dmd.31.6.762.
• [22] Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization. J Neurosci. 2009 Jun 3;29(22):7341-8.
• [23] Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010 Jan-Feb;19(1):4-16.
• [24] Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes. Drug Metab Dispos. 2010 Jan;38(1):40-5.
• [25] Effect of nonspecific binding to microsomes and metabolic elimination of buprenorphine on the inhibition of cytochrome P4502D6. Biol Pharm Bull. 2005 Feb;28(2):212-6.
• [26] Buprenorphine pharmacology review: update on transmucosal and long-acting formulations. J Addict Med. 2019 Mar/Apr;13(2):93-103.
• [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.
• [28] In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005 May;33(5):689-95.
• [29] Buprenorphine in cancer pain. Support Care Cancer. 2005 Nov;13(11):878-87.
• [30] Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro. Drug Metab Dispos. 2003 Jun;31(6):768-72.
• [31] 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.