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;

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.

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• Clonmel healthcare ltd
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• Mylan pharmaceuticals inc
• Parke davis div warner lambert co
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• Sandoz inc
• Superpharm corp
• Vangard laboratories inc div midway medical co
• Watson laboratories inc

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• Ivax Pharmaceuticals
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• Pharmacia Inc.
• Pharmedix
• Physicians Total Care Inc.
• UDL Laboratories

Synthesis Reference	Not Available
General Reference	Not Available

Type	small molecule

Classes

Sulfonylureas

Substructures

Sulfonylureas Sulfonyls Benzene and Derivatives Ureas and Derivatives Benzenesulfonamides Aromatic compounds Sulfonamides

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. Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us. Substrate Enzymes Product Tolbutamide Cytochrome P450 2C9 Cytochrome P450 2C19 4-Hydroxytolbutamide Details Tolbutamide Cytochrome P450 2C19 Cytochrome P450 2C8 Cytochrome P450 2C9 hydroxytolbutamide Details Tolbutamide 1-butyl-3-p-carboxyphenylsulfonylurea Details
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

Properties
State	solid
Experimental Properties	Property Value Source melting point 128.5 °C PhysProp water solubility 109 mg/L (at 37 °C) YALKOWSKY,SH & DANNENFELSER,RM (1992) logP 2.34 HANSCH,C ET AL. (1995) logS -3.39 ADME Research, USCD pKa 5.16 SANGSTER (1994)
Predicted Properties	Property Value Source water solubility 2.02e-01 g/l ALOGPS logP 2.04 ALOGPS logP 2.3 ChemAxon logS -3.1 ALOGPS pKa (strongest acidic) 4.33 ChemAxon physiological charge -1 ChemAxon hydrogen acceptor count 3 ChemAxon hydrogen donor count 2 ChemAxon polar surface area 75.27 ChemAxon rotatable bond count 4 ChemAxon refractivity 70.27 ChemAxon polarizability 29.1 ChemAxon

Drug	Interaction
Acebutolol	Acebutolol may decrease symptoms of hypoglycemia and increase the time required for the body to compensate for hypoglycemia.
Acenocoumarol	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Acenocoumarol. Consider alternate therapy or monitor for changes in Acenocoumarol therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Acetylsalicylic acid	Acetylsalicylic acid increases the effect of the sulfonylurea, tolbutamide.
Atenolol	The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
Bisoprolol	The beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Bosentan	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Bosentan. Consider alternate therapy or monitor for changes in Bosentan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Capecitabine	Capecitabine, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Capecitabine is initiated, discontinued or dose changed.
Carvedilol	The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
Celecoxib	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Celecoxib. Consider alternate therapy or monitor for changes in Celecobix therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Chloramphenicol	Chloramphenicol may increase the effect of sulfonylurea, tolbutamide.
Clofibrate	Clofibrate may increase the effect of sulfonylurea, tolbutamide.
Dapsone	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Dapsone. Consider alternate therapy or monitor for changes in Dapsone therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Delavirdine	Delavirdine, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Delavirdine is initiated, discontinued or dose changed.
Digoxin	Tolbutamide increases the effect of digoxin
Esmolol	The beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
Floxuridine	Floxuridine, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Floxuridine is initiated, discontinued or dose changed.
Fluconazole	Fluconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Fluconazole therapeutic and adverse effects if Delavirdine is initiated, discontinued or dose changed.
Fluorouracil	Fluorouracil, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Fluorouracil is initiated, discontinued or dose changed.
Fluoxetine	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Fluoxetine. Consider alternate therapy or monitor for changes in Fluoxetine therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Flurbiprofen	Flurbiprofen, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Flurbiprofen is initiated, discontinued or dose changed.
Fosphenytoin	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Fosphenytoin. Consider alternate therapy or monitor for changes in Fosphenytoin therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Gemfibrozil	Gemfibrozil, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Gemfibrozil is initiated, discontinued or dose changed.
Glimepiride	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Glimepiride. Consider alternate therapy or monitor for changes in Glimepiride therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Glipizide	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Glipizide. Consider alternate therapy or monitor for changes in Glipizide therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Ibuprofen	Ibuprofen, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Ibuprofen is initiated, discontinued or dose changed.
Indomethacin	Indomethacin, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Indomethacin is initiated, discontinued or dose changed.
Ketamine	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Ketamine. Consider alternate therapy or monitor for changes in Ketamine therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Ketoconazole	Ketoconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Ketoconazole is initiated, discontinued or dose changed.
Labetalol	The beta-blocker, labetalol, may decrease symptoms of hypoglycemia.
Losartan	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Losartan. Consider alternate therapy or monitor for changes in Losartan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Lumiracoxib	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Lumiracoxib. Consider alternate therapy or monitor for changes in Lumiracoxib therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Mefenamic acid	Mefanamic acid, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Mefanamic acid is initiated, discontinued or dose changed.
Mestranol	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Mestranol. Consider alternate therapy or monitor for changes in Mestranol therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Metoprolol	The beta-blocker, metoprolol, may decrease symptoms of hypoglycemia.
Miconazole	Miconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Miconazole is initiated, discontinued or dose changed.
Montelukast	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Montelukast. Consider alternate therapy or monitor for changes in Montelukast therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Nadolol	The beta-blocker, nadolol, may decrease symptoms of hypoglycemia.
Nateglinide	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Nateglinide. Consider alternate therapy or monitor for changes in Nateglinide therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Nicardipine	Nicardipine, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Nicardipine is initiated, discontinued or dose changed.
Oxprenolol	The beta-blocker, oxprenolol, may decrease symptoms of hypoglycemia.
Paclitaxel	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Paclitaxel. Consider alternate therapy or monitor for changes in Paclitaxel therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Phenylbutazone	Phenylbutazone increases the effect of the hypoglycemic agent
Phenytoin	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Phenytoin. Consider alternate therapy or monitor for changes in Phenytoin therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Pindolol	The beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
Piroxicam	Piroxicam, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Piroxicam is initiated, discontinued or dose changed.
Propranolol	The beta-blocker, propranolol, may decrease symptoms of hypoglycemia.
Rifampin	Rifampin may decrease the effect of sulfonylurea, tolbutamide.
Sitaxentan	Sitaxsentan, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Sitaxsentan is initiated, discontinued or dose changed.
Somatropin recombinant	Somatropin may antagonize the hypoglycemic effect of Tolbutamide. Dose adjustments of Tolbutamide may be required.
Sulfadiazine	Tolbutamide and Sulfadiazine are strong CYP2C9 inhibitors and substrates. Decreased metabolism and clearance of both agents may occur during concomitant therapy. Consider alternate therpy or monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or dose(s) changed.
Sulfamethoxazole	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Sulfamethoxazole. Consider alternate therapy or monitor for changes in Sulfamethoxazole therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Sulfinpyrazone	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Sulfinpyrazone. Consider alternate therapy or monitor for changes in Sulfinpyrazone therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Sulfisoxazole	Tolbutamide and Sulfisoxazole are strong CYP2C9 inhibitors and substrates. Decreased metabolism and clearance of both agents may occur during concomitant therapy. Consider alternate therpy or monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or dose(s) changed.
Tamoxifen	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tamoxifen. Consider alternate therapy or monitor for changes in Tamoxifen therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Timolol	The beta-blocker, timolol, may decrease symptoms of hypoglycemia.
Torasemide	Tolbutamide, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Tolbutamide is initiated, discontinued or dose changed.
Trimethoprim	The strong CYP2C9 inhibitor, Tolbutamide, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Tolbutamide is initiated, discontinued or dose changed.
Voriconazole	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Voriconazole. Consider alternate therapy or monitor for changes in Voriconazole therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Warfarin	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if tolbutamide is initiated, discontinued or dose changed.
Zafirlukast	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if tolbutamide is initiated, discontinued or dose changed.
Zopiclone	Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Zopiclone. Consider alternate therapy or monitor for changes in Zopiclone therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Not Available