General Information of Drug (ID: DMBDPY0)

Drug Name
Domperidone
Synonyms
Domperidon; Domperidona; Domperidonum; Motilium; Nauzelin; KW 5338; NCI299589; Costi (TN); D-122; Domperidona [INN-Spanish]; Domperidonum [INN-Latin]; HS-0067; KW-5338; Motilium (TN); Motillium (TN); Motinorm (TN); R 33,812; R-33812; R-33,812; Domperidone (JAN/USAN/INN); Domperidone [USAN:BAN:INN:JAN]; 4-(5-Chloro-2-oxo-1-benzimidazolinyl)-1-[3-(2-oxobenzimidazolinyl)propyl]piperidine; 5-Chloro-1-(1-(3-(2-oxo-1-benzimidazolinyl)propyl)-4-piperidyl)-2-benzimidazolinone; 5-Chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one; 5-Chloro-1-[1-[3-(2-oxo-1-benzimidazolinyl)propyl]-4-piperidyl]-2-benzimidazolinone; 5-chloro-1-(1-(3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one; 5-chloro-1-{1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one
Indication
Disease Entry ICD 11 Status REF
Gastrointestinal disease DE2Z Approved [1], [2]
Therapeutic Class
Antiemetics
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 0 Molecular Weight (mw) 425.9
Topological Polar Surface Area (xlogp) 3.9
Rotatable Bond Count (rotbonds) 5
Hydrogen Bond Donor Count (hbonddonor) 2
Hydrogen Bond Acceptor Count (hbondacc) 3
ADMET Property
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability [3]
Clearance
The drug present in the plasma can be removed from the body at the rate of 9.5 mL/min/kg [4]
Elimination
0% of drug is excreted from urine in the unchanged form [3]
Half-life
The concentration or amount of drug in body reduced by one-half in 7 hours [4]
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.3354 micromolar/kg/day [5]
Unbound Fraction
The unbound fraction of drug in plasma is 0.082% [4]
Vd
Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 3.4 L/kg [4]
Water Solubility
The ability of drug to dissolve in water is measured as 0.006 mg/mL [3]
Chemical Identifiers
Formula
C22H24ClN5O2
IUPAC Name
6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one
Canonical SMILES
C1CN(CCC1N2C3=C(C=C(C=C3)Cl)NC2=O)CCCN4C5=CC=CC=C5NC4=O
InChI
InChI=1S/C22H24ClN5O2/c23-15-6-7-20-18(14-15)25-22(30)28(20)16-8-12-26(13-9-16)10-3-11-27-19-5-2-1-4-17(19)24-21(27)29/h1-2,4-7,14,16H,3,8-13H2,(H,24,29)(H,25,30)
InChIKey
FGXWKSZFVQUSTL-UHFFFAOYSA-N
Cross-matching ID
PubChem CID
3151
ChEBI ID
CHEBI:31515
CAS Number
57808-66-9
DrugBank ID
DB01184
TTD ID
D0AV3G
VARIDT ID
DR00963
INTEDE ID
DR0527

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Dopamine D2 receptor (D2R) TTEX248 DRD2_HUMAN Antagonist [6], [7]

Drug Transporter (DTP)
DTP Name DTP ID UniProt ID MOA REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [8]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Substrate [9]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Substrate [10]
Cytochrome P450 1A2 (CYP1A2) DEJGDUW CP1A2_HUMAN Substrate [10]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Substrate [11]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Substrate [10]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Substrate [10]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Substrate [11]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease Gastrointestinal disease
ICD Disease Classification DE2Z
Molecule Name Molecule Type Gene Name p-value Fold-Change Z-score
Dopamine D2 receptor (D2R) DTT DRD2 2.50E-02 -0.08 -0.49
P-glycoprotein 1 (ABCB1) DTP P-GP 9.39E-02 1.07E-01 2.80E-01
Cytochrome P450 2C8 (CYP2C8) DME CYP2C8 1.82E-04 -1.35E-01 -5.84E-01
Cytochrome P450 2B6 (CYP2B6) DME CYP2B6 4.88E-01 -1.69E-05 -1.28E-04
Cytochrome P450 1A2 (CYP1A2) DME CYP1A2 7.36E-01 1.62E-02 1.08E-01
Cytochrome P450 3A5 (CYP3A5) DME CYP3A5 9.96E-01 -3.17E-03 -1.84E-02
Cytochrome P450 2D6 (CYP2D6) DME CYP2D6 7.30E-01 -1.91E-02 -1.41E-01
Cytochrome P450 3A4 (CYP3A4) DME CYP3A4 1.04E-02 6.29E-02 3.54E-01
Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This Drug

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: 965).
2 A systematic review of the efficacy of domperidone for the treatment of diabetic gastroparesis. Clin Gastroenterol Hepatol. 2008 Jul;6(7):726-33.
3 BDDCS applied to over 900 drugs
4 Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
5 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
6 Screening of domperidone in wastewater by high performance liquid chromatography and solid phase extraction methods. Talanta. 2006 Jan 15;68(3):928-31.
7 The significance of disordered gastric emptying. Z Gastroenterol. 1986 Sep;24 Suppl 2:45-54.
8 Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates. J Pharm Pharmacol. 2004 Aug;56(8):967-75.
9 Characterization of CYP3A isozymes involved in the metabolism of domperidone: role of cytochrome b5 and inhibition by ketoconazole. Drug Metab Lett. 2010 Apr;4(2):95-103.
10 Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro. Br J Clin Pharmacol. 2004 Sep;58(3):277-87.
11 Drug Interactions Flockhart Table
12 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.
13 Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
14 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.
15 Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
16 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.
17 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.
18 Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
19 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.
20 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.
21 Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
22 Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
23 Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
24 Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
25 PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
26 The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
27 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.
28 Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
29 Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
30 Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
31 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.
32 CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
33 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.
34 Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
35 Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
36 Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
37 Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
38 Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer. J Urol. 2008 Dec;180(6):2389-95.
39 Human prostate CYP3A5: identification of a unique 5'-untranslated sequence and characterization of purified recombinant protein. Biochem Biophys Res Commun. 1999 Jul 14;260(3):676-81.
40 Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
41 Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. Drug Metab Dispos. 2007 Oct;35(10):1754-8.
42 Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
43 Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
44 Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
45 Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.
46 The role of cytochrome P450 3A (CYP3A) isoform(s) in oxidative metabolism of testosterone and benzphetamine in human adult and fetal liver. J Steroid Biochem Mol Biol. 1993 Jan;44(1):61-7.
47 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
48 Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos. 2004 Feb;32(2):259-66.
49 The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
50 Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
51 Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003 Sep;13(9):565-75.
52 Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry. 2004 Dec 14;43(49):15379-92.
53 Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8.
54 PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
55 Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
56 Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
57 Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol. 1999 Sep 1;58(5):787-96.
58 Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
59 Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
60 Drugs that may have potential CYP2B6 interactions.
61 Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 Jul;37(7):717-24.
62 Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone metabolism by cytochrome P450 2B6. Drug Metab Dispos. 2005 Dec;33(12):1760-4.
63 PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70.
64 Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes: studies on amitriptyline as a model substrate. J Pharmacol Exp Ther. 2001 Apr;297(1):326-37.
65 Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
66 MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
67 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.
68 Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
69 Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
70 Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
71 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.
72 The Detection of Dopamine Gene Receptors (DRD1-DRD5) Expression on Human Peripheral Blood Lymphocytes by Real Time PCR. Iran J Allergy Asthma Immunol. 2004 Dec;3(4):169-74.
73 Dopaminergic synapses in the matrix of the ventrolateral striatum after chronic haloperidol treatment. Synapse. 2002 Aug;45(2):78-85.
74 CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics. 2007 Nov;17(11):989-93.
75 Synthesis and in vitro binding of N-phenyl piperazine analogs as potential dopamine D3 receptor ligands. Bioorg Med Chem. 2005 Jan 3;13(1):77-87.
76 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: 3639).
77 Receptor reserve-dependent properties of antipsychotics at human dopamine D2 receptors. Eur J Pharmacol. 2009 Apr 1;607(1-3):35-40.
78 [The benzamides tiapride, sulpiride, and amisulpride in treatment for Tourette's syndrome]. Nervenarzt. 2007 Mar;78(3):264, 266-8, 270-1.
79 Modulatory role of dopamine D2 receptors and fundamental role of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral... Eur J Pharmacol. 2009 Mar 15;606(1-3):90-3.
80 Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
81 Randomized clinical comparison of perospirone and risperidone in patients with schizophrenia: Kansai Psychiatric Multicenter Study. Psychiatry Clin Neurosci. 2009 Jun;63(3):322-8.