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

General Information of Drug (ID: DM1BV7W)

• Drug Name: Aliskiren Drug Info
• Synonyms: Rasilez; SPP 100; Rasilez (TN); Tekturna (TN); Aliskiren (USAN/INN); (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyl-2-(propan-2-yl)nonanamide; (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-2-propan-2-ylnonanamide; (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]octanamide; Octanamide, .delta.-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-.gamma.-hydroxy-4-methoxy-3-(3-methoxypropoxy)-.alpha.,.zeta.-bis(1-methylethyl)-, [.alpha.S-(alpha.R*,.gamma.R*,.delta.R*,.zeta.R*)]

Indication

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[1] , [2] , [3]

• Therapeutic Class: Antihypertensive Agents
• Cross-matching ID:
  PubChem CID: 5493444
  ChEBI ID: CHEBI:601027
  CAS Number: CAS 173334-57-1
  TTD Drug ID: DM1BV7W
  VARIDT Drug ID: DR00061
  INTEDE Drug ID: DR0065
  ACDINA Drug ID: D00019

Molecule-Related Drug Atlas

Drug(s) Metabolized By Cytochrome P450 3A4 (CYP3A4)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Solid tumour/cancer	2A00-2F9Z	Approved	[8]
Progesterone	DMUY35B	Premature labour	JB00	Approved	[9]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[10]
Estradiol	DMUNTE3	Breast cancer	2C60-2C65	Approved	[11]
Acetaminophen	DMUIE76	Pain	MG30-MG3Z	Approved	[12]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[13]
Etoposide	DMNH3PG	Solid tumour/cancer	2A00-2F9Z	Approved	[14]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[15]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[9]
Verapamil	DMA7PEW	Hypertension	BA00-BA04	Approved	[16]

Drug(s) Transported By P-glycoprotein 1 (ABCB1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amoxicillin	DMUYNEI	Bacterial infection	1A00-1C4Z	Approved	[17]
Doxorubicin	DMVP5YE	Solid tumour/cancer	2A00-2F9Z	Approved	[18]
Methotrexate	DM2TEOL	leukaemia	2A60-2B33	Approved	[19]
Folic acid	DMEMBJC	Folate-deficiency anemia	3A02.Y	Approved	[20]
Fluorouracil	DMUM7HZ	Solid tumour/cancer	2A00-2F9Z	Approved	[19]
Cisplatin	DMRHGI9	Solid tumour/cancer	2A00-2F9Z	Approved	[19]
Progesterone	DMUY35B	Premature labour	JB00	Approved	[21]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[19]
Estradiol	DMUNTE3	Breast cancer	2C60-2C65	Approved	[22]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[23]

Drug(s) Transported By Organic anion transporting polypeptide 2B1 (SLCO2B1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[24]
L-glutamic acid	DM4PUDW	Schizophrenia	6A20	Approved	[25]
Sulfasalazine	DMICA9H	Irritable bowel syndrome	DD91.0	Approved	[26]
Etoposide	DMNH3PG	Solid tumour/cancer	2A00-2F9Z	Approved	[27]
Pravastatin	DM6A0X7	Hypercholesterolaemia	5C80.0	Approved	[28]
Atorvastatin	DMF28YC	Cardiovascular disease	BA00-BE2Z	Approved	[29]
Cerivastatin	DMXCM7H	Hyperlipidaemia	5C80	Approved	[30]
Pitavastatin calcium	DM1UJO0	Dyslipidemia	5C80-5C81	Approved	[31]
Digoxin	DMQCTIH	Arrhythmia	BC9Z	Approved	[32]
Rosuvastatin	DMMIQ7G	Hypercholesterolaemia	5C80.0	Approved	[33]

Drug(s) Targeting Angiotensinogenase renin (REN)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Remikiren	DMNAKLY	Hypertension	BA00-BA04	Approved	[34]
SPP-600	DMOVQP8	Hypertension	BA00-BA04	Phase 2	[35]
TAK-272	DM81UAZ	Type-2 diabetes	5A11	Phase 2	[36]
SR-43845	DMTOCIV	Glaucoma/ocular hypertension	9C61	Phase 2	[37]
CP-80794	DMT3ORQ	Hypertension	BA00-BA04	Phase 2	[38]
VTP-27999	DMQEOD6	Hypertension	BA00-BA04	Phase 1	[39]
ACT-178882	DMOZ3AT	Cardiovascular disease	BA00-BE2Z	Phase 1	[40]
CARD-024	DM4SNK8	Cardiovascular disease	BA00-BE2Z	Phase 1	[41]
FK-906	DMTEW80	Hypertension	BA00-BA04	Discontinued in Phase 2	[42]
Enalkiren	DMDAS5B	Glaucoma/ocular hypertension	9C61	Discontinued in Phase 2	[43]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Angiotensinogenase renin (REN)	TTB2MXP	RENI_HUMAN	Inhibitor	[4]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[5]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[7]

References

• [1] 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: 4812).
• [2] 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
• [3] Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63.
• [4] Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patie... J Renin Angiotensin Aldosterone Syst. 2009 Sep;10(3):157-67.
• [5] Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol. 2011 May;71(5):718-26.
• [6] Effects of the inhibition of intestinal P-glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys. Biopharm Drug Dispos. 2015 Jan;36(1):15-33.
• [7] Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515-31.
• [8] 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.
• [9] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [10] 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.
• [11] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [12] 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.
• [13] 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.
• [14] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [15] 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.
• [16] 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.
• [17] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [18] MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
• [19] 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.
• [20] Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
• [21] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
• [22] Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
• [23] 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.
• [24] Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun. 2000 Jun 24;273(1):251-60.
• [25] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.60.1.20)
• [26] Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP. J Pharm Sci. 2017 Sep;106(9):2688-2694.
• [27] Identification of drugs and drug metabolites as substrates of multidrug resistance protein 2 (MRP2) using triple-transfected MDCK-OATP1B1-UGT1A1-MRP2 cells. Br J Pharmacol. 2012 Mar;165(6):1836-1847.
• [28] Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004 Feb;308(2):438-45.
• [29] Human platelets express organic anion-transporting peptide 2B1, an uptake transporter for atorvastatin. Drug Metab Dispos. 2009 May;37(5):1129-37.
• [30] pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm. 2011 Aug 1;8(4):1303-13.
• [31] Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos. 2006 Jul;34(7):1229-36.
• [32] Drug Interactions in Infectious Diseases.
• [33] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [34] Functional expression of the renin-angiotensin system in human podocytes. Am J Physiol Renal Physiol. 2006 Mar;290(3):F710-9.
• [35] Effect of SPP 635, a renin inhibitor, on intraocular pressure in glaucomatous monkey eyes. Exp Eye Res. 2012 Jan;94(1):146-9.
• [36] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033655)
• [37] Effects of a renin inhibitor, SR 43845, and of captopril on blood pressure and plasma active renin in conscious sodium-replete macaca. J Hypertens Suppl. 1989 Apr;7(2):S33-5.
• [38] Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril. J Cardiovasc Pharmacol. 1992 Jul;20(1):75-82.
• [39] New Developments in the Pharmacological Treatment of Hypertension: Dead-End or a Glimmer at the Horizon . Curr Hypertens Rep. 2015; 17(6): 42.
• [40] Drug-drug interaction study of ACT-178882, a new renin inhibitor, and diltiazem in healthy subjects. Clin Drug Investig. 2013 Mar;33(3):207-13.
• [41] 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. (Target id: 2413).
• [42] Antihypertensive efficacy of FK906, a novel human renin inhibitor. Clin Ther. 1993 May-Jun;15(3):539-48.
• [43] Comparative effects of three different potent renin inhibitors in primates. Hypertension. 1993 Jul;22(1):9-17.