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Identification
Name Chlorpropamide
Accession Number DB00672 (APRD00029)
Type small molecule
Groups approved
Description

Chlorpropamide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the sulfonylurea class of insulin secretagogues, which act by stimulating β cells of the pancreas to release insulin. Sulfonylureas increase both basal insulin secretion and meal-stimulated insulin release. Medications in this class differ in their dose, rate of absorption, duration of action, route of elimination and binding site on their target pancreatic β cell receptor. Sulfonylureas also increase peripheral glucose utilization, decrease hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, though less so than insulin. Due to their mechanism of action, sulfonylureas may cause hypoglycemia and require consistent food intake to decrease this risk. The risk of hypoglycemia is increased in elderly, debilitated and malnourished individuals. Chlorpropamide is not recommended for the treatment of NIDDM as it increases blood pressure and the risk of retinopathy (UKPDS-33). Up to 80% of the single oral dose of chlorpropramide is metabolized, likely in the liver; 80-90% of the dose is excreted in urine as unchanged drug and metabolites. Renal and hepatic dysfunction may increase the risk of hypoglycemia.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Chlorporpamide
Brand names
  • Adiaben
  • Apo-Chlorpropamide
  • Asucrol
  • Catanil
  • Chlorodiabina
  • Chloronase
  • Chloropropamide
  • Chlorpropamid
  • Chlorpropamide Bp/ Usp
  • Clorpropamide
  • Diabaril
  • Diabechlor
  • Diabenal
  • Diabenese (Pfizer)
  • Diabeneza
  • Diabet-Pages
  • Diabetoral
  • Diabinese
  • Diamel Ex
  • Dynalase
  • Glisema
  • Glucamide
  • Insulase
  • Meldian
  • Melitase
  • Mellinese
  • Millinese
  • Novo-Propamide
  • Oradian
  • Stabinol
Brand name mixtures Not Available
Categories
  • Hypoglycemic Agents
  • Sulfonylureas
  • Antidiabetic
CAS number 94-20-2
Weight Average: 276.74
Monoisotopic: 276.033540689
Chemical Formula C10H13ClN2O3S
InChI Key InChIKey=RKWGIWYCVPQPMF-UHFFFAOYSA-N
InChI
InChI=1S/C10H13ClN2O3S/c1-2-7-12-10(14)13-17(15,16)9-5-3-8(11)4-6-9/h3-6H,2,7H2,1H3,(H2,12,13,14)
Plain Text
IUPAC Name
1-[(4-chlorobenzene)sulfonyl]-3-propylurea
SMILES
CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes
  • Sulfonylureas
Substructures
  • Sulfonylureas
  • Sulfonyls
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Aryl Halides
  • Benzenesulfonamides
  • Halobenzenes
  • Aromatic compounds
  • Sulfonamides
Pharmacology
Indication For treatment of NIDDM in conjunction with diet and exercise.
Pharmacodynamics Chlorpropamide, a second-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Chlorpropamide is twice as potent as the related second-generation agent glipizide.
Mechanism of action Sulfonylureas such as chlorpropamide bind to ATP-sensitive potassium channels on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.
Absorption Readily absorbed from the GI tract. Peak plasma concentrations occur within 2-4 hours and the onset of action occurs within one hour. The maximal effect of chlorpropamide is seen 3-6 hours following oral administration.
Volume of distribution Not Available
Protein binding Highly bound to plasma proteins.
Metabolism

Up to 80% of dose is metabolized likely through the liver to to 2-hydroxylchlorpropamide (2-OH CPA), p-chlorobenzenesulfonylurea (CBSU), 3-hydroxylchlorpropamide (3-OH CPA), and p-chlorobenzenesulfonamide (CBSA); CBSA may be produced by decomposition in urine. It is unknown whether chlorpropamide metabolites exert hypoglycemic effects.

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 3-Hydroxychlorpropamide
Prostaglandin G/H synthase 1 p-Chlorobenzene sulfonyl urea
Cytochrome P450 2C9 2-Hydroxychlorpropamide 2-hydroxylation
Cytochrome P450 2C19 2-Hydroxychlorpropamide 2-hydroxylation
Route of elimination 80-90% of a single oral dose is excreted in the urine as unchaged drug and metabolites within 96 hours.
Half life Approximately 36 hours with interindividual variation ranging from 25-60 hours. Duration of effect persists for at least 24 hours.
Clearance Not Available
Toxicity IPN-RAT LD50 580 mg/kg
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Barr laboratories inc
  • Clonmel healthcare ltd
  • Duramed pharmaceuticals inc sub barr laboratories inc
  • Halsey drug co inc
  • Ivax pharmaceuticals inc
  • Mylan pharmaceuticals inc
  • Par pharmaceutical inc
  • Pliva inc
  • Sandoz inc
  • Superpharm corp
  • Teva pharmaceuticals usa inc
  • Usl pharma inc
  • Watson laboratories inc
  • Pfizer laboratories div pfizer inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral 100 mg
Tablet Oral 250 mg
Prices
Unit description Cost Unit
Diabinese 250 mg tablet 1.34 USD tablet
Diabinese 100 mg tablet 0.61 USD tablet
Chlorpropamide 250 mg tablet 0.46 USD tablet
Chlorpropamide 100 mg tablet 0.33 USD tablet
Patents Not Available
Properties
State solid
Melting point 127 - 129 oC
Experimental Properties
Property Value Source
water solubility Solubility at pH 6 is 2.2 mg/ml PhysProp
logP 1.8 PhysProp
logS -3.03 [ADME Research, USCD] PhysProp
Predicted Properties
Property Value Source
water solubility 1.57e-01 g/l ALOGPS
logP 2.15 ALOGPS
logP 1.94 ChemAxon Molconvert
logS -3.25 ALOGPS
pKa 17.07 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 75.27 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 65.43 ChemAxon Molconvert
polarizability 27.05 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00271 Link_out
PubChem Compound 2727 Link_out
PubChem Substance 46506402 Link_out
ChemSpider 2626 Link_out
ChEBI 3650 Link_out
ChEMBL 3650 Link_out
Therapeutic Targets Database DAP000923 Link_out
PharmGKB PA448966 Link_out
Drug Product Database 156728 Link_out
RxList http://www.rxlist.com/cgi/generic2/chlorpro.htm Link_out
Drugs.com http://www.drugs.com/cdi/chlorpropamide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Chlorpropamide Link_out
ATC Codes
  • A10BB02
AHFS Codes
  • 68:20.20
PDB Entries Not Available
FDA label Not Available
MSDS show (35.8 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Food reduces the rate of absorption.
  • Take 30 minutes before meal.
Targets

1. ATP-binding cassette transporter sub-family C member 8

Pharmacological action: yes
Actions: inhibitor

Putative subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K+ channels and insulin release

Organism class: human
UniProt ID: Q09428 Link_out
Gene: ABCC8 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mizuno CS, Chittiboyina AG, Kurtz TW, Pershadsingh HA, Avery MA: Type 2 diabetes and oral antihyperglycemic drugs. Curr Med Chem. 2008;15(1):61-74. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: 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. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: 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. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Prostaglandin G/H synthase 1

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: 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. Epub 2009 Sep 1. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ibrahim S, Peggins J, Knapton A, Licht T, Aszalos A: Influence of antipsychotic, antiemetic, and Ca(2+) channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation. J Pharmacol Exp Ther. 2000 Dec;295(3):1276-83. Pubmed

2. Oligopeptide transporter, small intestine isoform

Actions: inhibitor

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Terada T, Sawada K, Saito H, Hashimoto Y, Inui K: Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2. Eur J Pharmacol. 2000 Mar 24;392(1-2):11-7. Pubmed

3. Oligopeptide transporter, kidney isoform

Actions: inhibitor

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides

UniProt ID: Q16348 Link_out
Gene: SLC15A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Terada T, Sawada K, Saito H, Hashimoto Y, Inui K: Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2. Eur J Pharmacol. 2000 Mar 24;392(1-2):11-7. Pubmed

4. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Uwai Y, Saito H, Hashimoto Y, Inui K: Inhibitory effect of anti-diabetic agents on rat organic anion transporter rOAT1. Eur J Pharmacol. 2000 Jun 16;398(2):193-7. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on September 15, 2011 11:09

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.