Details of the Drug

General Information of Drug (ID: DMC50ME)

• Drug Name: Debrisoquin
• Synonyms: Debrisochinum; Debrisoquina; Debrisoquine; Debrisoquinum; Declinax; Equitonil; Isocaramidine; Tendor; DEBRISOQUIN SULFATE; Debrisoquin hemisulfate; Debrisoquine sulfate; Isocaramidine sulfate; Debrisoquina [INN-Spanish]; Debrisoquine [INN:BAN]; Debrisoquinum [INN-Latin]; Ro 5-3307/1; Sulfuric acid compound with 3,4-dihydro-2(1H)-isoquinolinecarboximidamide (1:1); 1,2,3, 4-Tetrahydro-isoquinoline-2-carboxamidine sulfate; 2(1H)-Isoquinolinecarboxamidine, 3,4-dihydro-(7CI,8CI); 2(1H)-Isoquinolinecarboxamidine, 3,4-dihydro-, sulfate (2:1); 2(1H)-Isoquinolinecarboximidamide, 3,4-dihydro-, sulfate (2:1); 2-Amidino-1,2,3,4-tetrahydroisoquinoline; 3,4-Dihydro-2(1H)-isoquinolinecarboxamidine; 3,4-Dihydro-2(1H)-isoquinolinecarboxamidine sulfate (2:1); 3,4-Dihydro-2(1H)-isoquinolinecarboximidamide; 3,4-Dihydro-2(1H;)-isoquinoline carboxamidine sulfate; 3,4-dihydro-1H-isoquinoline-2-carboximidamide; 3,4-dihydroisoquinoline-2(1H)-carboximidamide

Indication

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

• Therapeutic Class: Antihypertensive Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 175.23
  Topological Polar Surface Area (xlogp); 0.8
  Rotatable Bond Count (rotbonds); 1
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 1
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [2]
  Elimination: 12% of drug is excreted from urine in the unchanged form [2]
  Metabolism: The drug is metabolized via the hepatic [3]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 24.457 micromolar/kg/day [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 29 mg/mL [2]
• Chemical Identifiers:
  Formula: C10H13N3
  IUPAC Name: 3,4-dihydro-1H-isoquinoline-2-carboximidamide
  Canonical SMILES: C1CN(CC2=CC=CC=C21)C(=N)N
  InChI: InChI=1S/C10H13N3/c11-10(12)13-6-5-8-3-1-2-4-9(8)7-13/h1-4H,5-7H2,(H3,11,12)
  InChIKey: JWPGJSVJDAJRLW-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 2966
  ChEBI ID: CHEBI:34665
  CAS Number: 1131-64-2
  DrugBank ID: DB04840
  TTD ID: D0MP5H
  VARIDT ID: DR01479
  INTEDE ID: DR0427

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Adrenergic neuron (AD neuro)	TTT04VN	NOUNIPROTAC	Blocker	[5]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[6]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Substrate	[8]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Substrate	[9]

References

• [1] Drug information of Debrisoquin, 2008. eduDrugs.
• [2] BDDCS applied to over 900 drugs
• [3] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [4] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [5] Guanethidine and related agents. 3. Antagonism by drugs which inhibit the norepinephrine pump in man. J Clin Invest. 1970 Aug;49(8):1596-604.
• [6] The prototypic pharmacogenetic drug debrisoquine is a substrate of the genetically polymorphic organic cation transporter OCT1. Biochem Pharmacol. 2012 May 15;83(10):1427-34.
• [7] Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res. 1999 Mar;16(3):408-14.
• [8] Functional analysis of CYP2D6.31 variant: homology modeling suggests possible disruption of redox partner interaction by Arg440His substitution. Proteins. 2005 May 1;59(2):339-46.
• [9] 4-Hydroxylation of debrisoquine by human CYP1A1 and its inhibition by quinidine and quinine. J Pharmacol Exp Ther. 2002 Jun;301(3):1025-32.
• [10] Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitutions on steroid hydroxylase specificity. Pharmacogenetics. 2000 Aug;10(6):519-30.
• [11] Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
• [12] Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007 Jul;56(7):887-94.
• [13] Preferred orientations in the binding of 4'-hydroxyacetanilide (acetaminophen) to cytochrome P450 1A1 and 2B1 isoforms as determined by 13C- and 15N-NMR relaxation studies. J Med Chem. 1994 Mar 18;37(6):860-7.
• [14] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [15] Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
• [16] A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio. Clin Chem Lab Med. 2005;43(7):702-6.
• [17] Cytochromes P450 in crustacea. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Nov;121(1-3):157-72.
• [18] Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone. Biochem J. 1998 Apr 1;331 ( Pt 1):273-81.
• [19] Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab. 2007 Aug;8(6):554-62.
• [20] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [21] Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
• [22] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [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] 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.
• [25] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [26] Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
• [27] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [28] Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
• [29] Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
• [30] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [31] MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
• [32] 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.
• [33] Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
• [34] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
• [35] Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
• [36] 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.
• [37] Are organic cation transporters capable of transporting prostaglandins? Naunyn Schmiedebergs Arch Pharmacol. 2005 Aug;372(2):125-30.
• [38] Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther. 2006 Nov;319(2):879-86.
• [39] Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia. Leuk Lymphoma. 2008 Apr;49(4):639-42.
• [40] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [41] Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett. 2006 Mar 8;234(1):4-33.
• [42] Upregulation of histone acetylation reverses organic anion transporter 2 repression and enhances 5-fluorouracil sensitivity in hepatocellular carcinoma
• [43] Comparison of type I and type II organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5.
• [44] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [45] Influx Transport of Cationic Drug at the Blood-Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants. Biol Pharm Bull. 2017;40(8):1139-1145.
• [46] Characterization of bradykinin-induced endothelium-independent contraction in equine basilar artery. J Vet Pharmacol Ther. 2009 Jun;32(3):264-70.