DIPHENOXYLATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C30H32N2O2
Molecular Weight	452.5873
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCOC(=O)C1(CCN(CCC(C#N)(C2=CC=CC=C2)C3=CC=CC=C3)CC1)C4=CC=CC=C4

InChI

InChIKey=HYPPXZBJBPSRLK-UHFFFAOYSA-N

InChI=1S/C30H32N2O2/c1-2-34-28(33)29(25-12-6-3-7-13-25)18-21-32(22-19-29)23-20-30(24-31,26-14-8-4-9-15-26)27-16-10-5-11-17-27/h3-17H,2,18-23H2,1H3

HIDE SMILES / InChI

Description
Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f170584a-1072-4fd7-b1dc-6756703483b9
Curator's Comment: description was created based on several sources, including ISBN-13: 978-0323055932

Diphenoxylate is an opioid drug used for the treatment of acute diarrhea. The drug is used in combination with atropine and marketed under names Lomotil and Diphenoxylate hydrochloride and atropine sulfate. Diphenoxylate is biotransformed in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood. The drug exerts its action by activating mu opioid receptors of intestinal mucosa.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mu-type opioid receptor 61 Target ID: P35372\|\|\|G8XRH8\|\|\|Q5TDA1\|\|\|Q9UN57 Gene ID: 4988.0 Gene Symbol: OPRM1 Target Organism: Homo sapiens (Human) Sources: ISBN-13: 978-0323055932	Agonist 2678

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute diarrhea 4 Sources: https://www.hpra.ie/img/uploaded/swedocuments/PA%20899-7-1%20PIL%20-2162562-11062015155951-635696351923400000.pdf	Curative		Approved 8429	LOMOTIL Approved Use Lomotil is effective as adjunctive therapy in the management of diarrhea. Launch Date 1960

C_max

Value	Dose	Co-administered	Analyte	Population
622.68 ng/mL EXPERIMENT https://www.researchgate.net/publication/254338105_Determination_of_diphenoxylate_in_rat_plasma_by_gradient_elution_LC-ESI-MS	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		DIPHENOXYLATE plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED
9.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/5026379	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DIPHENOXYLATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
7157.61 ng × h/mL EXPERIMENT https://www.researchgate.net/publication/254338105_Determination_of_diphenoxylate_in_rat_plasma_by_gradient_elution_LC-ESI-MS	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		DIPHENOXYLATE plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
10.68 h EXPERIMENT https://www.researchgate.net/publication/254338105_Determination_of_diphenoxylate_in_rat_plasma_by_gradient_elution_LC-ESI-MS	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		DIPHENOXYLATE plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED
2.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/5026379	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		DIPHENOXYLATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
15.5% OTHER https://go.drugbank.com/drugs/DB01081			DIPHENOXYLATE unknown	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
20 mg 1 times / day steady, oral Studied dose Dose: 20 mg, 1 times / day Route: oral Route: steady Dose: 20 mg, 1 times / day Co-administed with:: atropine sulfate(0.025 mg) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf
300 mg 1 times / day steady, oral (max) Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf	Other AEs: Drug dependence... Other AEs: Drug dependence Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf

AEs

AE	Significance	Dose	Population
Drug dependence		300 mg 1 times / day steady, oral (max) Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012462s048lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 inhibitor 1587	inducer 389	inducer 97 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Ca2+ channels 57 CYP2B6 810	P-gp 1537	CYP2C19 293 CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2C19 1553	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: abstract	minor	yes (co-administration study) Comment: diphenoxylate decreased omeprazole AUC and Cmax Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: abstract
CYP2B6 1001	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0	no	no (co-administration study) Comment: diphenoxylate had no effect on buproprion AUC and Cmax Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0
CYP2D6 1891	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0	no	no (co-administration study) Comment: diphenoxylate had no effect on metroprolol AUC and Cmax Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0
CYP3A4 1925	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0	no	no (co-administration study) Comment: diphenoxylate had no effect on testosterone AUC and Cmax Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: 18805.0
Ca2+ channels 60	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0041008X03003727 Page: 136.0	unlikely
CYP1A2 1692	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: abstract	yes	yes (co-administration study) Comment: diphenoxylate decreased phenacetin AUC and Cmax Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: abstract
CYP2C9 1819	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: abstract	yes	yes (co-administration study) Comment: diphenoxylate decreased tolbutamide AUC and Cmax Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694398/ Page: abstract

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0041008X03003727 Page: 135.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249760/ Page: abstract

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4639	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4639
ChemicalBook	CB3301641	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3301641
ZINC	ZINC000003830716	http://zinc15.docking.org/substances/ZINC000003830716

PubMed

Title	Date	PubMed
[Irritable colon].	2001 Aug 20	11530562
Irritable bowel syndrome: update on pathogenesis and management.	2002 Jan-Mar	12116690
The efficacy of octreotide in the therapy of acute radiation-induced diarrhea: a randomized controlled study.	2002 Sep 1	12182992
Potential roles of P-gp and calcium channels in loperamide and diphenoxylate transport.	2003 Nov 15	14613723
Protective effect of Arque-Ajeeb on acute experimental diarrhoea in rats.	2004 Jul 6	15238156
Comparison between prospective and retrospective evaluation of Crohn's disease activity index.	2005 May	15842587
Evolutionary explanations in medical and health profession courses: are you answering your students' "why" questions?	2005 May 10	15885137
Lomotil dependence: a note of caution.	2005 Nov-Dec	16483040
Tissue distribution of loperamide and N-desmethylloperamide following a fatal overdose.	2005 Oct	16419413
Long-acting octreotide in the treatment of diarrhea after pelvic pouch surgery.	2006 Dec	17115310
Treatment of diarrhea in patients with inflammatory bowel disease: concepts and cautions.	2007	18192964
Loperamide: a pharmacological review.	2007	18192961
[Treating travelers' diarrhea. When should medication be given?].	2007 Dec	18097699
In vivo evaluation of antidiarrhoeal activity of Rhus semialata fruit extract in rats.	2007 Oct 27	20162061
Methylnaltrexone in the treatment of opioid-induced constipation.	2008	21677823
[Topic: Treating travelers' diarrhea. When should medication be given?].	2008 Jun	18537033
Long-term outcome of in-patients with substance use disorders: A study from North India.	2008 Oct	19823613
Hashish body packing: a case report.	2009	19724651
Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma.	2009 Feb 18	20616894
[Roles of enteric nervous system neurotransmitters and interstitial cells of Cajal in the colon in slow transit constipation in rats].	2009 Jun	19558815
An Open-Label, Noncomparative, Multicenter Study to Evaluate Efficacy and Safety of NASHA/Dx Gel as a Bulking Agent for the Treatment of Fecal Incontinence.	2010	21234379
Development of a list of potentially inappropriate drugs for the korean elderly using the delphi method.	2010 Dec	21818443
Antidiarrhoeal activity of carbazole alkaloids from Murraya koenigii Spreng (Rutaceae) seeds.	2010 Jan	19695314
Antidiarrheal activity of extracts and compound from Trilepisium madagascariense stem bark.	2010 Jun	20871767
Effect of an antidiabetic polysaccharide from Inula japonica on constipation in normal and two models of experimental constipated mice.	2010 Nov	20564501

Patents

Sample Use Guides

In Vivo Use Guide

Adults: The recommended initial dosage is two Lomotil tablets (each tablet contains 2,5 mg diphenoxylate hydrochloride) four times daily; Dosage schedule for children: The recommended initial total daily dosage of Lomotil liquid for children is 0.3 to 0.4 mg/kg, administered in four divided doses.

Route of Administration: Oral

In Vitro Use Guide

Unknown

Name

Type

Language

DIPHENOXYLATE

Official Name

English

diphenoxylate [INN]

Common Name

English

ISONIPECOTIC ACID, 1-(3-CYANO-3,3-DIPHENYLPROPYL)-4-PHENYL-, ETHYL ESTER

Common Name

English

DIPHENOXYLATE [MI]

Common Name

English

DIPHENOXYLATE [VANDF]

Common Name

English

DIPHENOXYLATE [HSDB]

Common Name

English

1-(3-CYANO-3,3-DIPHENYLPROPYL)-4-PHENYLPIPERIDINE-4-CARBOXYLIC ACID ETHYL ESTER

Systematic Name

English

Diphenoxylate [WHO-DD]

Common Name

English

IDS-ND-016

Code

English

4-PIPERIDINECARBOXYLIC ACID, 1-(3-CYANO-3,3-DIPHENYLPROPYL)-4-PHENYL-, ETHYL ESTER

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000178374