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Identification
Name Tolbutamide
Accession Number DB01124 (APRD00267)
Type small molecule
Groups approved
Description

Tolbutamide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It is structurally similar to acetohexamide, chlorpropamide and tolazamide and 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. Tolbutamide appears to be metabolized in the liver. Tolbutamide and its metabolites are excreted in urine (75-85%) and feces.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Aglicid
  • Apo-Tolbutamide
  • Arkozal
  • Artosin
  • Artozin
  • Butamid
  • Butamide
  • Diaben
  • Diabetamid
  • Diabetol
  • Diabuton
  • Diasulfon
  • Dirastan
  • Dolipol
  • Drabet
  • Glyconon
  • Ipoglicone
  • Mobenol
  • Novo-Butamide
  • Orabet
  • Oralin
  • Orezan
  • Orinase
  • Orinase Diagnostic
  • Orinaz
  • Oterben
  • Pramidex
  • Rastinon
  • Restinon
  • Sk-tolbutamide
  • Tol-Tab
  • Tolbusal
  • Tolbutamid
  • Toluina
  • Tolumid
  • Toluvan
  • Tolylsulfonylbutylurea
  • Willbutamide
Brand name mixtures Not Available
Categories
  • Hypoglycemic Agents
  • Sulfonylureas
CAS number 64-77-7
Weight Average: 270.348
Monoisotopic: 270.103813142
Chemical Formula C12H18N2O3S
InChI Key InChIKey=JLRGJRBPOGGCBT-UHFFFAOYSA-N
InChI
InChI=1S/C12H18N2O3S/c1-3-4-9-13-12(15)14-18(16,17)11-7-5-10(2)6-8-11/h5-8H,3-4,9H2,1-2H3,(H2,13,14,15)
Plain Text
IUPAC Name
3-butyl-1-[(4-methylbenzene)sulfonyl]urea
SMILES
CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1
Plain Text
Mass Spec show (9.1 KB)
Taxonomy
Kingdom Organic
Classes
  • Sulfonylureas
Substructures
  • Sulfonylureas
  • Sulfonyls
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Benzenesulfonamides
  • Aromatic compounds
  • Sulfonamides
Pharmacology
Indication For treatment of NIDDM (non-insulin-dependent diabetes mellitus) in conjunction with diet and exercise.
Pharmacodynamics Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work.
Mechanism of action Sulfonylureas lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose.
Absorption Readily absorbed following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH.
Volume of distribution Not Available
Protein binding Approximately 95% bound to plasma proteins.
Metabolism

Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 2C9 4-Hydroxytolbutamide 4-hydroxylation
Cytochrome P450 2C9 hydroxytolbutamide hydroxylation 523 150.28
Cytochrome P450 2C8 hydroxytolbutamide hydroxylation 0 0
Cytochrome P450 2C19 4-Hydroxytolbutamide 4-hydroxylation
Cytochrome P450 2C19 hydroxytolbutamide hydroxylation 395 223.6
Route of elimination Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 hours.
Half life Approximately 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas.
Clearance Not Available
Toxicity Oral, mouse: LD50 = 2600 mg/kg
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pharmacia and upjohn co
  • Alra laboratories inc
  • Ascot hosp pharmaceuticals inc div travenol laboratories inc
  • Barr laboratories inc
  • Clonmel healthcare ltd
  • Ivax pharmaceuticals inc
  • Mylan pharmaceuticals inc
  • Parke davis div warner lambert co
  • Purepac pharmaceutical co
  • Sandoz inc
  • Superpharm corp
  • Vangard laboratories inc div midway medical co
  • Watson laboratories inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral 500 mg
Prices
Unit description Cost Unit
Tolbutamide 500 mg tablet 0.4 USD tablet
Patents Not Available
Properties
State solid
Melting point 128.5 oC
Experimental Properties
Property Value Source
water solubility 109 mg/L PhysProp
logP 2.2 PhysProp
logS -3.39 [ADME Research, USCD] PhysProp
pKa 5.16 Various sources
Predicted Properties
Property Value Source
water solubility 2.02e-01 g/l ALOGPS
logP 2.04 ALOGPS
logP 2.30 ChemAxon Molconvert
logS -3.13 ALOGPS
pKa 18.11 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 75.27 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 70.27 ChemAxon Molconvert
polarizability 29.10 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00380 Link_out
KEGG Compound C07148 Link_out
PubChem Compound 5505 Link_out
PubChem Substance 46508421 Link_out
ChemSpider 5304 Link_out
ChEBI 27999 Link_out
ChEMBL 27999 Link_out
Therapeutic Targets Database DAP000136 Link_out
PharmGKB PA451718 Link_out
Drug Product Database 156663 Link_out
Drugs.com http://www.drugs.com/cdi/tolbutamide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tolbutamide Link_out
ATC Codes
  • A10BB03
  • V04CA01
AHFS Codes
  • 68:20.20
PDB Entries Not Available
FDA label Not Available
MSDS show (73.9 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
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

2. ATP-sensitive inward rectifier potassium channel 1

Pharmacological action: unknown
Actions: inhibitor

In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium

Organism class: human
UniProt ID: P48048 Link_out
Gene: KCNJ1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Proks P, Jones P, Ashcroft FM: Interaction of stilbene disulphonates with cloned K(ATP) channels. Br J Pharmacol. 2001 Mar;132(5):973-82. Pubmed
  2. Smith PA, Proks P: Inhibition of the ATP-sensitive potassium channel from mouse pancreatic beta-cells by surfactants. Br J Pharmacol. 1998 Jun;124(3):529-39. Pubmed
  3. Liu X, Singh BB, Ambudkar IS: ATP-dependent activation of K(Ca) and ROMK-type K(ATP) channels in human submandibular gland ductal cells. J Biol Chem. 1999 Aug 27;274(35):25121-9. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: substrate, inhibitor

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. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. 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
  4. Lasker JM, Wester MR, Aramsombatdee E, Raucy JL: Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys. 1998 May 1;353(1):16-28. Pubmed

2. Cytochrome P450 2C8

Actions: substrate, inhibitor

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. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. 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. Lasker JM, Wester MR, Aramsombatdee E, Raucy JL: Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin, and omeprazole hydroxylations. Arch Biochem Biophys. 1998 May 1;353(1):16-28. Pubmed

4. Cytochrome P450 2C18

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

UniProt ID: P33260 Link_out
Gene: CYP2C18 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
Transporters

1. 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

2. Solute carrier organic anion transporter family member 1A2

Actions: inhibitor

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Shitara Y, Sugiyama D, Kusuhara H, Kato Y, Abe T, Meier PJ, Itoh T, Sugiyama Y: Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21a5)-mediated transport. Pharm Res. 2002 Feb;19(2):147-53. Pubmed

3. 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

4. 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

5. Solute carrier organic anion transporter family member 2B1

Actions: substrate

Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost

UniProt ID: O94956 Link_out
Gene: SLCO2B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, Sawada Y: Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos. 2005 Apr;33(4):518-23. Epub 2005 Jan 7. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 19, 2011 12:10

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.