Last updated
Clinical data
Trade names Orinase
AHFS/ Monograph
MedlinePlus a682481
License data
  • AU:C
Routes of
Oral (tablet)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 96%
Metabolism Hepatic (CYP2C19-mediated)
Elimination half-life 4.5 to 6.5 hours
Excretion Renal
  • N-[(Butylamino)carbonyl]-4-methylbenzenesulfonamide
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.541 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H18N2O3S
Molar mass 270.35 g·mol−1
3D model (JSmol)
Melting point 128.5 to 129.5 °C (263.3 to 265.1 °F)
  • O=S(=O)(c1ccc(cc1)C)NC(=O)NCCCC
  • 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) Yes check.svgY

Tolbutamide is a first-generation potassium channel blocker, sulfonylurea oral hypoglycemic medication. This drug may be used in the management of type 2 diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas.


It is not routinely used due to a higher incidence of adverse effects compared to newer, second-generation sulfonylureas, such as Glibenclamide. It generally has a short duration of action due to its rapid metabolism, so is safe for use in older people.

It was discovered in 1956. [1]

Side effects

  1. Hypoglycemia
  2. Weight gain
  3. Hypersensitivity: cross-allergicity with sulfonamides
  4. Drug interactions (especially first-generation drugs): Increased hypoglycemia with cimetidine, insulin, salicylates, and sulfonamides

Salicylates displace tolbutamide from its binding site on plasma binding proteins which lead to increase in free tolbutamide concentration, thus hypoglycemic shock. [2]


Orinase was developed by Upjohn Co. at a time when the primary medical treatment for diabetes was insulin injections. Eli Lilly had a lock on the market for insulin production at the time. The practical applicability of Orinase, like that of other treatments for disease states detected by paraclinical signs (such as lab test results) rather than clinically observable signs or patient-reported symptoms, benefited from increased sensitivity and availability of testing (in this instance, urinary glucose testing and later also fingerstick blood glucose testing). Milton Moskowitz (editor in 1961 of Drug and Cosmetic Industry) claimed that the introduction of Orinase, "expanded the total market by bringing under medical care diabetics who were formerly not treated." [3] It did this by changing the mindset about diabetes even more than insulin had. Treatment of this chronic disease was no longer seen as a mere slowing of "inexorable degeneration", but instead viewed through "a model of surveillance and early detection." [3] :84

Orinase and other sulfonylureas emerged from European pharmaceutical research into antibiotics, specifically from attempts to develop sulfa compounds. One of the contenders for a new sulfa antibiotic had serious side effects during clinical trials at the University of Montpellier including blackouts, convulsions, and coma, side effects not observed with any other drugs in the sulfa cohort. An insulin researcher at the same university heard of these side effects and recognized them as common results of hypoglycemia. The resulting class of drugs for lowering blood sugar came to be known as the sulfonylureas, starting with Orinase and still in use today in other forms.

Unfortunately for diabetics dependent on insulin as a treatment for their condition, this research at Montpellier occurred in the early 1940s and was significantly disrupted by the German occupation of France during World War II. Development of these compounds was taken over by German pharmaceutical companies, which were obviously disinclined to share their bounty with nations upon which they were waging war. The German research was, in turn, disrupted by Germany's defeat in 1945 and the partition of Germany into East and West Germany. The sulfonylureas were trapped in East Germany. In 1952, someone smuggled a sample to a West German pharmaceutical company and research resumed. Clinical trials in diabetics began in 1954 in Berlin. In 1956, two different sulfonylureas were brought to market in Germany under the trade names Nadisan and Rastinon. American pharmaceutical companies in the postwar period had been seeking to establish business relations with the remnants of German pharmaceutical giants weakened by the war and partition of Germany. Upjohn (based in Kalamazoo until its purchase by Pharmacia in the 1990s) made deals with Hoechst, maker of Rastinon. The result was a cross-licensing agreement which produced Orinase.

Upjohn stood to open up a whole new arena of treatment for diabetes, one with a built-in and sustainable market, i.e. patient population. Just as two German companies brought sulfonylureas to market within the same year, Upjohn discovered Eli Lilly had begun clinical trials for carbutamide, another oral hypoglycemic. Upjohn pushed for large-scale clinical trials from 1955–1957, enrolling over 5,000 patients at multiple sites.

Upjohn's formulation was preferred when the Lilly formulation demonstrated evidence of toxicity in parallel trials at the Joslin Clinic. Lilly pulled carbutamide and halted development, leaving the field open for Upjohn to market its new treatment. In 1956, Upjohn filed for approval from the Food and Drug Administration. Jeremy A. Greene found the application's size – 10,580 pages in 23 volumes with 5,786 cases reports – was necessary to "render visible the relatively small improvements provided in less severe forms of diabetes." Indeed, Orinase was marketed by Upjohn not as a cure-all for all diabetics, but specifically as a treatment that was "not an oral insulin" and "did not work in all diabetics". Those were the instructions for marketing given to Upjohn's salespeople. As indicated by the FDA application, Orinase had been demonstrated "not to be effective in severe diabetes, but only in milder cases of the disease." [3] :93 Orinase was one of a new class of drugs (including treatments for hypertension and hypercholesterolemia) aimed at providing marginal benefits over existing treatments for patients who had not previously been a target market for pharmaceuticals. As blood sugar testing for diagnosis of diabetes became more widespread, a curious side effect occurred: because blood sugar testing is not absolutely definitive in diagnoses of diabetes, more people were receiving borderline tests regarding their glycemic status. These borderline persons could be considered as being at risk for diabetes – prediabetic. Prediabetic patients have elevated blood sugar, but normal levels of sugar in their urine (glycosuria). Upjohn saw an opportunity to benefit and definitely market to a yet-greater expansion of the diabetic population, beyond even the "hidden diabetics" revealed by earlier public health campaigns. Upjohn also found a new use for Orinase: as a diagnostic. Orinase Diagnostic was added to the Orinase product line and, by 1962, was being sold as means of detecting prediabetes in that an abnormal response to Orinase following administration of cortisone in a "stress test" could be taken to indicate prediabetes. Orinase thus not only served to detect a previously hidden patient population, but also detected a patient population most likely to be interested in Orinase as a treatment for their newly diagnosed prediabetes. By the late 1960s, Orinase Diagnostic was withdrawn and the drug reverted to its therapeutic purpose. By that point, prediabetes had become a diagnosable and treatable condition which had dramatically increased the market for Orinase.

Orinase began to fall out of favor in May 1970 when asymptomatic prediabetics on long-term regimens of Orinase began to see news reports (beginning with the Washington Post ) that Orinase may have serious side effects including death from cardiovascular problems, according to a long-term study. In many cases, patients learned of this before their physicians, and also before FDA could advise relabeling the medication or suggesting alterations in appropriate usage. The question of whether Orinase did or did not increase cardiovascular problems has not been conclusively settled. The result was that Orinase and other medical treatments for prediabetes were "rolled back" by the FDA and practitioners in an attempt to focus on symptomatic patients for whom the risks of treatment might be balanced by the symptoms of the disease.

Pharmacia and Upjohn (now merged) stopped making Orinase in 2000, though a generic is still available and occasionally used.

Historical consequences

The history of tolbutamide has had a lasting effect on medicine and the pharmaceutical industry. Patients today are still diagnosed with prediabetes, many of them managing to delay the onset of diabetes through dietary and lifestyle changes, but many also have the option to take metformin, which demonstrated a 31% reduction in three-year incidence of development of diabetes relative to placebo. [4] While impressive, the lifestyle-modification arm of that same trial demonstrated a 58% reduction. [5]

See also

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

The following is a glossary of diabetes which explains terms connected with diabetes.

<span class="mw-page-title-main">Glimepiride</span> Medication

Glimepiride is an antidiabetic medication within the sulfonylurea class, primarily prescribed for the management of type 2 diabetes. It is regarded as a second-line option compared to metformin, due to metformin's well-established safety and efficacy. Use of glimepiride is recommended in conjunction with lifestyle modifications such as diet and exercise. It is taken by mouth, reaching a peak effect within three hours and lasting for about a day.

Drugs used in diabetes treat diabetes mellitus by decreasing the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Sulfonylurea</span> Class of organic compounds used in medicine and agriculture

Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea, a dehydrogenated derivative of urea). The side chains R1 and R2 distinguish various sulfonylureas. Sulfonylureas are the most widely used herbicide.

Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. Along with neonatal diabetes, MODY is a form of the conditions known as monogenic diabetes. While the more common types of diabetes involve more complex combinations of causes involving multiple genes and environmental factors, each forms of MODY are caused by changes to a single gene (monogenic). GCK-MODY and HNF1A-MODY are the most common forms.

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

<span class="mw-page-title-main">Chlorpropamide</span> Chemical compound

Chlorpropamide is an antidiabetic drug, belonging to the sulfonylurea class of organic compounds. It is used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea.

<span class="mw-page-title-main">Diabetic hypoglycemia</span> Medical condition

Diabetic hypoglycemia is a low blood glucose level occurring in a person with diabetes mellitus. It is one of the most common types of hypoglycemia seen in emergency departments and hospitals. According to the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP), and based on a sample examined between 2004 and 2005, an estimated 55,819 cases involved insulin, and severe hypoglycemia is likely the single most common event.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin twice daily or once weekly.

<span class="mw-page-title-main">Biguanide</span> Chemical compound

Biguanide is the organic compound with the formula HN(C(NH)NH2)2. It is a colorless solid that dissolves in water to give highly basic solution. These solutions slowly hydrolyse to ammonia and urea.

<span class="mw-page-title-main">Gliclazide</span> Chemical compound

Gliclazide, sold under the brand name Diamicron among others, is a sulfonylurea type of anti-diabetic medication, used to treat type 2 diabetes. It is used when dietary changes, exercise, and weight loss are not enough. It is taken by mouth.

A diabetic diet is a diet that is used by people with diabetes mellitus or high blood sugar to minimize symptoms and dangerous complications of long-term elevations in blood sugar.

<span class="mw-page-title-main">Gliquidone</span> Chemical compound

Gliquidone is an anti-diabetic medication in the sulfonylurea class. It is classified as a second-generation sulfonylurea. It is used in the treatment of diabetes mellitus type 2. It is marketed by the pharmaceutical company Boehringer Ingelheim (Germany).

Richard K. Bernstein is a physician and an advocate for a low-carbohydrate diabetes diet to help achieve normal blood sugars for diabetics. Bernstein has type 1 diabetes. His private medical practice in Mamaroneck, New York is devoted solely to treating diabetes and prediabetes.

Chronic Somogyi rebound is a contested explanation of phenomena of elevated blood sugars experienced by diabetics in the morning. Also called the Somogyi effect and posthypoglycemic hyperglycemia, it is a rebounding high blood sugar that is a response to low blood sugar. When managing the blood glucose level with insulin injections, this effect is counter-intuitive to people who experience high blood sugar in the morning as a result of an overabundance of insulin at night.

Dysglycemia is a general definition for any abnormalities in blood glucose levels. They include hyperglycemia, hypoglycemia, impaired glucose tolerance test, impaired fasting glucose, among others.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.


  1. Walker SR (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN   978-94-009-2659-2.
  2. Kalra S (2015). "Sulfonylureas and their use in clinical practice". Veterinary Record Open. Termedia Publishing. 1 (1): e000080. doi:10.1136/vetreco-2014-000080. PMC   4562452 . PMID   26392882.
  3. 1 2 3 Greene JA (2007). Prescribing by Numbers: Drugs and the Definition of Disease. Baltimore, MD.: Johns Hopkins University Press. ISBN   978-0-8018-8477-1.
  4. Lawrence WL (24 February 1957). "Science in Review: Drug for the Treatment of Diabetes Tested And Found of Great Importance". The New York Times .
  5. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (February 2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". The New England Journal of Medicine. 346 (6): 393–403. doi:10.1056/NEJMoa012512. PMC   1370926 . PMID   11832527.