Drug/Small Molecule:

tolbutamide

Overview

IUPAC Name:	1-butyl-3-(4-methylphenyl)sulfonylurea
Trade 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
PharmGKB Accession Id:	PA451718

Description

A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p290)

Indication

Used as an oral hypoglycemic agent in non-insulin-dependent (type 2) Diabetes Miletus with adult onset.

ATC Therapeutic Categories

• A10BB:Sulfonamides, urea derivatives
• V04CA:Tests for diabetes

Pharmacology and Interactions

Mechanism Of Action

Sulfonylureas lower blood glucose in patients with type 2 diabetes 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.

Pharmacology

Tolbutamide, a second-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.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic

Protein Binding

96%

Absorption

Well absorbed. Absorption is unaltered if taken with food but is increased with high pH.

Half Life

4.5-6.5 hours in normal adults

Toxicity

Oral, mouse: LD₅₀ = 2600 mg/kg

Chemical Properties

Chemical Formula:

C₁₂H₁₈N₂O₃S

SMILES Code:

CCCCNC(=O)NS(=O)(=O)c1ccc(cc1)C

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

270.348 / 270.1038

In-Depth Annotations ()

1. rs1799853 at chr10:96692037 in CYP2C9
   This variant has been shown to influence warfarin dose as well as affecting the clearance of several other drugs.

   Variant Name:

   CYP2C9*2; CYP2C9:144Arg>Cys

   Related Drugs:

   fluvastatin, glipizide, phenytoin, tolbutamide, warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforCYP2C9-111
   

2. rs1057910 at chr10:96731043 in CYP2C9
   This variant has been shown to correlate significantly with warfarin dose as well as affecting the clearance of several other drugs.

   Variant Name:

   CYP2C9*3; CYP2C9:359Ile>Leu

   Related Drugs:

   fluvastatin, glipizide, phenytoin, tolbutamide, warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforCYP2C9-222
   

Curated Annotations ()

1. rs41291556 at chr10:96525163 in CYP2C19
   This variant is the defining SNP for CYP2C19*8 and leads to decreased activity and poor metabolizer (PM) phenotype.This variant is associated with a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide in vitro.

   Variant Name:

   CYP2C19:358T>C; 12711T>C; W120R; T358C

   Related Drugs:

   mephenytoin, tolbutamide

   Evidence:

   PMID:10411572
   

2. rs56337013 at chr10:96602485 in CYP2C19
   This variant is the defining SNP for CYP2C19*5 and contributes to the S-mephenytoin poor metabolizer phenotype in caucasians and chinese. The Arg433 to Trp mutation in the heme-binding region essentially abolishes CYP2C19 activity toward S-mephenytoin and tolbutamide.

   Variant Name:

   CYP2C19:1297C>T; R433W

   Related Drugs:

   mephenytoin, tolbutamide

   Evidence:

   PMID:10022751
   

Curated Information

The following genes are in curated knowledge about this drug.

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

• CYP1A2
• CYP2C19
• CYP2A6
• CYP2D6
• CYP2C9
• CYP2C8
• CYP2E1

Drug Targets

• KCNJ1

PharmGKB Curated Pathways

• Anti-diabetic drug pathway (Potassium channel inhibitors PD)

Curated Information

The following drugs are in curated knowledge about this drug.

	Drug	Relationship	Evidence
	fluvastatin	PK	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Diabetes Mellitus	CO PD PK	Publications, Pathways
	Diabetes Mellitus, Type 2	PD PK	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. Physicochemical determinants of human renal clearance
2. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

LinkOuts

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Non-Curated Publications

A list of non-curated publications that mention this drug is available.