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Tolbutamide
Clinical data
Trade namesOrinase
AHFS/Drugs.comMonograph
MedlinePlusa682481
License data
Pregnancy
category
  • AU: C
Routes of
administration		Oral (tablet)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding96%
MetabolismHepatic (CYP2C19-mediated)
Elimination half-life4.5 to 6.5 hours
ExcretionRenal
Identifiers
  • N-[(Butylamino)carbonyl]-4-methylbenzenesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.541 Edit this at Wikidata
Chemical and physical data
FormulaC12H18N2O3S
Molar mass270.35 g·mol−1
3D model (JSmol)
Melting point128.5 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) checkY
  • Key:JLRGJRBPOGGCBT-UHFFFAOYSA-N checkY
  (verify)

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

[edit]

Side effects include:[medical citation needed]

  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]

History

[edit]

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

[edit]

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

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Tolbutamide

View on Grokipedia
from Grokipedia
Tolbutamide is a first-generation antidiabetic medication used in conjunction with diet and exercise to manage mellitus by lowering blood glucose levels in patients with non-insulin-dependent diabetes. It functions primarily by stimulating the release of insulin from the beta cells of the , an effect that depends on the presence of functioning pancreatic beta cells. The development of tolbutamide traces back to the mid-20th century, when researchers observed unexpected hypoglycemic effects in antibiotics during the pre-World War II era, leading to targeted synthesis of compounds. In 1946, studies confirmed that these agents triggered insulin secretion from pancreatic beta cells, paving the way for clinical use. Tolbutamide became the first to be commercially introduced in 1956 in , marketed under the brand name Orinase in 500 mg tablets, and it played a pioneering role in oral antidiabetic therapy before the advent of second-generation . Although effective for glycemic control, tolbutamide has notable pharmacokinetic properties, including rapid absorption and a short of about 4 to 8 hours, primarily metabolized in the liver to inactive compounds and excreted via the kidneys. It is no longer marketed in the United States, though it may still be available in other countries for patients unable to tolerate newer agents. Common side effects include , gastrointestinal upset, and rare hematologic reactions, underscoring the need for careful monitoring in clinical use.

Medical uses

Indications

Tolbutamide is primarily indicated for the management of mellitus in adults whose blood glucose levels are not adequately controlled by diet and exercise alone, particularly in mild cases where is moderate. It is no longer available but may still be used in other countries where accessible. As a first-generation , it serves as an adjunct therapy to improve glycemic control in non-insulin-dependent diabetes by stimulating insulin secretion from pancreatic beta cells. Historically, tolbutamide was used in the tolbutamide tolerance test, an intravenous diagnostic procedure to identify or latent by evaluating the rate of blood glucose decline following drug administration, which reflects beta-cell responsiveness. This test carried risks of severe and is no longer standard practice, having been superseded by safer diagnostic methods such as oral glucose tolerance tests or ; its associated was discontinued in 2015. Cardiovascular hazards have been associated with long-term use but are not directly relevant to this acute diagnostic application. Where available, sulfonylureas are considered second-line options per international guidelines for patients intolerant to or unresponsive to metformin, but only when benefits outweigh potential risks in select cases. Early clinical trials in the mid-1950s provided foundational evidence of tolbutamide's efficacy, showing significant reductions in fasting and postprandial blood glucose levels in approximately 80% of patients with mild, maturity-onset over initial treatment periods of several months. These studies, involving hundreds of participants, confirmed its utility in achieving normoglycemia without insulin in responsive individuals, paving the way for oral in .

Dosage and administration

Tolbutamide is administered orally as tablets, typically in strengths of 500 mg, and is usually taken once daily in the morning or in divided doses to align with meals, which helps minimize gastrointestinal upset. The standard initial dose for adults with is 1 to 2 grams per day, given as a single dose or divided into two or three doses (for example, 500 mg to 1.5 grams per meal), with based on the patient's glucose response. The maintenance dose ranges from 0.25 to 3 grams daily, though doses exceeding 2 grams are rarely necessary, and the maximum recommended daily dose is 3 grams. Dosage adjustments are required for patients with renal or hepatic impairment, as well as for elderly, debilitated, or malnourished individuals, starting with conservative initial and maintenance doses to reduce the risk of . Regular monitoring of glucose and HbA1c levels is essential to assess and guide dose adjustments, alongside on recognizing and managing symptoms of , such as shakiness or . When discontinuing tolbutamide, gradual tapering is recommended under medical supervision to prevent rebound hyperglycemia, with close monitoring of blood glucose during the transition.

Pharmacology

Mechanism of action

Tolbutamide, a first-generation sulfonylurea, exerts its hypoglycemic effects primarily by stimulating insulin secretion from pancreatic beta cells. It achieves this by binding with high affinity to the sulfonylurea receptor 1 (SUR1) subunit of ATP-sensitive potassium (KATP) channels, which are composed of SUR1 and the inwardly rectifying potassium channel subunit Kir6.2. This binding inhibits channel activity, reducing potassium efflux and leading to partial closure of the KATP channels. The inhibition of KATP channels causes membrane depolarization in beta cells, which activates voltage-gated calcium channels and promotes calcium influx into the cell. The resulting increase in intracellular calcium concentrations triggers the of insulin-containing granules, thereby enhancing insulin release into the bloodstream. Unlike some second-generation , tolbutamide specifically targets SUR1-containing channels and does not significantly interact with SUR2 isoforms found in other tissues, limiting its effects to pancreatic beta cells. This process is glucose-independent once initiated but requires ambient glucose for maximal insulin secretion. Tolbutamide's mechanism is entirely dependent on the presence of functioning beta cells, rendering it ineffective in conditions such as type 1 diabetes mellitus or advanced type 2 diabetes where beta-cell failure has occurred. While its primary mechanism is the stimulation of insulin secretion, tolbutamide may also have extrapancreatic effects, such as decreasing hepatic insulin metabolism, reducing glucagon secretion, and increasing peripheral insulin sensitivity; however, these are considered secondary to the increase in circulating insulin levels. Additionally, tolbutamide's short duration of action, owing to its rapid hepatic metabolism to inactive carboxytolbutamide, distinguishes it from second-generation sulfonylureas like glibenclamide, which exhibit prolonged activity due to slower clearance and higher potency.

Pharmacokinetics

Tolbutamide is rapidly and completely absorbed from the gastrointestinal tract following oral administration, with bioavailability exceeding 90%. Peak plasma concentrations are typically achieved within 2 to 4 hours after dosing, and absorption is not significantly affected by food intake. The drug is highly bound to plasma proteins, primarily albumin, at levels of 92% to 96%. Its volume of distribution is approximately 0.13 L/kg, indicating limited distribution outside the plasma compartment. Tolbutamide crosses the placenta, potentially exposing the fetus to the drug during pregnancy. However, it exhibits limited penetration across the blood-brain barrier due to poor partitioning into brain tissue. Metabolism occurs primarily in the liver through oxidation by the enzyme , forming the inactive metabolite hydroxytolbutamide, which is further oxidized to the derivative carboxytolbutamide. plays a minimal role in this process, contrary to occasional misconceptions. Elimination of tolbutamide is characterized by a plasma of 4.5 to 6.5 hours in healthy individuals. The drug is primarily excreted via the kidneys as metabolites, with 75% to 85% of the dose recovered in as carboxytolbutamide and hydroxytolbutamide, while less than 1% is excreted unchanged. Pharmacokinetics can be altered by certain factors, including reduced clearance in elderly patients due to age-related declines in hepatic function. impairs , leading to prolonged exposure and increased risk of . Additionally, individuals with poor metabolizer genotypes, such as *3/*3, exhibit significantly reduced clearance (approximately 0.15 L/h compared to 0.97 L/h in *1/*1 wild-type), resulting in higher plasma levels and extended .

Adverse effects

Common adverse effects

Tolbutamide, as a first-generation sulfonylurea, is associated with several common adverse effects that are typically mild and self-limiting, though they may require dose adjustment or monitoring. is the most frequent adverse effect of tolbutamide , resulting from its stimulation of insulin release from pancreatic beta cells. Symptoms often include shakiness, sweating, , irritability, , and hunger, which can escalate to severe episodes if untreated. The risk is heightened in elderly patients, those with skipped meals, or individuals engaging in unaccustomed exercise, as tolbutamide's short may still lead to notable blood glucose fluctuations. Incidence rates vary, but post-marketing surveillance and clinical experience indicate it occurs in a clinically significant proportion of users, particularly during initial or dose escalation. Regular is recommended, especially in at-risk patients. Gastrointestinal disturbances represent another common issue, affecting approximately 1.4% of patients in early clinical trials. These primarily manifest as , , and epigastric discomfort or fullness, which are often dose-related and may resolve upon dosage reduction. Such effects are thought to arise from local or direct impact on gastric . Weight gain is a frequent consequence of tolbutamide use, averaging about 2.8 kg in treated patients, attributable to improved glycemic control and the anabolic effects of elevated insulin levels. This occurs in a substantial number of individuals over months of therapy, as reflected in systematic reviews of antidiabetic agents. Dermatologic reactions, such as pruritus or mild , are less common but reported in about 1.1% of patients from data. These allergic skin manifestations, including or urticaria, are usually transient and may subside without intervention, though persistent cases warrant discontinuation. Post-marketing surveillance has confirmed their manageability in most instances.

Serious adverse effects

Tolbutamide, like other , is associated with rare but serious hematologic adverse effects, including , , , , , and , with incidence not well-established in reported cases. These reactions can lead to severe complications such as bleeding, infection, or , necessitating regular monitoring of (CBC) during therapy. Discontinuation of the drug typically results in resolution, though prompt medical intervention is required for symptomatic patients. Hepatic toxicity from tolbutamide manifests rarely as or elevated liver enzymes, often reversible upon . Case reports document instances of developing weeks to months after initiation, with histological findings consistent with and minimal hepatocellular damage. should be monitored periodically, particularly in patients with preexisting hepatic impairment, as these effects occur in fewer than 0.1% of users. Hypersensitivity reactions to tolbutamide can include severe cutaneous eruptions or , though these are uncommon. As a containing a moiety, tolbutamide carries a theoretical risk of in patients with allergies, prompting caution and potential avoidance in such individuals despite limited evidence of immunologic . Symptoms may escalate to systemic involvement, requiring immediate discontinuation and supportive care. Cardiovascular concerns with tolbutamide stem primarily from the University Group Diabetes Program (UGDP) study, which reported an increased risk of ischemic events and cardiovascular mortality in patients treated with the drug compared to or insulin. This finding, involving a elevation of approximately 2.5-fold for cardiac deaths, remains debated due to methodological critiques, including baseline imbalances and study design issues, but has influenced warnings in product labeling. Current guidelines recommend before initiating therapy in diabetic patients. Other serious effects include , which overlaps with hematologic toxicities and heightens infection risk, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to . SIADH has been noted particularly in elderly patients, with symptoms of fluid retention and resolving after drug cessation. These rare events have frequency not reported, underscoring the need for vigilance in long-term use. Periodic monitoring may be advisable in at-risk patients.

Drug interactions

Pharmacokinetic interactions

Tolbutamide undergoes primary metabolism via the cytochrome P450 enzyme CYP2C9 to form the inactive metabolite hydroxytolbutamide, which is subsequently excreted by the kidneys, making its disposition sensitive to alterations in these pathways. Inhibitors of CYP2C9 can significantly elevate tolbutamide plasma concentrations and prolong its half-life by impeding hepatic metabolism. For instance, fluconazole potently inhibits CYP2C9, resulting in a 109% increase in tolbutamide's area under the plasma concentration-time curve (AUC) in healthy volunteers. Similarly, amiodarone inhibits CYP2C9 activity, leading to reduced tolbutamide clearance and higher systemic exposure. Sulfonamides, particularly sulfaphenazole, exhibit strong competitive inhibition of CYP2C9-mediated tolbutamide hydroxylation, with in vitro studies predicting up to a 4.8-fold rise in tolbutamide AUC and clinical data confirming substantial reductions in clearance (approximately 80%). Phenylbutazone also inhibits CYP2C9 and has been shown in human trials to approximately double tolbutamide's elimination half-life following pretreatment. Inducers of accelerate tolbutamide's metabolism, thereby decreasing its plasma levels and potentially reducing therapeutic efficacy. Rifampin, a known inducer, more than doubles tolbutamide's metabolic clearance in clinical studies, as measured by increased elimination rates after repeated dosing. Tolbutamide is approximately 90-95% bound to plasma proteins, and concurrent administration of displacers can increase the unbound fraction, thereby enhancing its pharmacological effects through elevated free drug concentrations. Sulfonamides and are classic examples of such displacers, with historical clinical reports documenting potentiated tolbutamide activity due to this mechanism, often in combination with metabolic inhibition. Drugs that impair renal function, such as nonsteroidal drugs (NSAIDs), may reduce the clearance of hydroxytolbutamide, leading to prolonged overall exposure to tolbutamide's effects, particularly in patients with compromised function.

Pharmacodynamic interactions

Tolbutamide, a first-generation , exhibits pharmacodynamic interactions with various agents that enhance or antagonize its glucose-lowering effects through additive or opposing physiological actions. Beta-blockers, particularly non-selective ones, can potentiate by masking its adrenergic warning symptoms such as and tremors, while also potentially impairing hepatic glucose counter-regulation, thereby prolonging recovery from low blood glucose episodes. Salicylates, including high-dose aspirin, may enhance tolbutamide's hypoglycemic action via an unclear mechanism possibly involving increased insulin secretion or sensitivity, increasing the risk of severe . Concomitant use with insulin results in additive stimulation of insulin release and , necessitating careful dose adjustments to avoid excessive . In contrast, certain agents antagonize tolbutamide's effects by promoting . diuretics counteract insulin action at the cellular level, reducing tolbutamide's efficacy and often requiring upward dose adjustments or additional monitoring. s induce and elevate blood glucose through glucocorticoid-mediated effects on , potentially necessitating temporary insulin therapy during high-dose use alongside tolbutamide. impairs pancreatic insulin secretion, further elevating glucose levels and diminishing tolbutamide's therapeutic response. Alcohol presents a unique pharmacodynamic risk with tolbutamide, as acute intake can inhibit hepatic and , leading to severe and prolonged ; additionally, like tolbutamide may provoke a disulfiram-like reaction characterized by flushing, , and due to aldehyde dehydrogenase inhibition. Tolbutamide also interacts bidirectionally with , potentiating both anticoagulation (via enhanced warfarin effects) and (with studies in users showing a 22% increased odds of serious hypoglycemic events when combined with , particularly in new initiators). Clinical management involves close during initiation or dose changes of interacting agents, with recommendations to adjust tolbutamide doses proactively for hyperglycemic antagonists like thiazides or corticosteroids, and to avoid or limit alcohol consumption to prevent acute risks. For warfarin co-therapy, enhanced surveillance of both INR and glucose levels is advised due to the dual potentiation.

Chemistry

Chemical structure and properties

Tolbutamide is a derivative with the C12H18N2O3SC_{12}H_{18}N_{2}O_{3}S and a of 270.35 g/mol. Its IUPAC name is NN-[(butylamino)carbonyl]-4-methylbenzenesulfonamide, and it is also known as 1-butyl-3-(4-methylphenylsulfonyl), featuring a core substituted with a butyl chain at the nitrogen and a p-tolyl group on the . The compound has the CAS number 64-77-7 and CID 5505. Tolbutamide appears as a white to off-white crystalline powder. It has a of 128–130 °C and a of approximately 1.245 g/cm³. The compound is practically insoluble in , with a of about 0.04 mg/mL at pH 7.4, but it is soluble in organic solvents such as (approximately 30 mg/mL), acetone, and . Tolbutamide is stable when stored at (15–30 °C) in a tightly closed and is sensitive to , though it is non-hygroscopic.

Synthesis

Tolbutamide is synthesized through the reaction of p-toluenesulfonyl with in an solvent such as dioxane, as described in the original process developed by The Company in the . The is added dropwise to the solution at , followed by stirring at 80°C for one hour to complete the formation. This single-step method yields the product upon evaporation of the solvent, precipitation with water, and purification by dissolution in aqueous and acidification with . An alternative synthetic route involves the initial sulfonylation of with p-toluenesulfonyl chloride to form the N-butyl-p-toluenesulfonamide intermediate, followed by formation via reaction with under basic conditions. This multi-step approach, often conducted in or similar solvents, provides flexibility for laboratory-scale preparation and aligns with early developmental methods prior to optimization. The industrial process, patented by , emphasizes the isocyanate-amine coupling for scalability and efficiency in producing pharmaceutical-grade tolbutamide. Yields typically range from 70% to 80%, with final purification achieved by recrystallization from to ensure high purity. Modern variants focus on greener and faster methods, such as microwave-assisted synthesis, which reduces reaction time from 30 minutes at 55°C under conventional heating to just a few minutes, achieving yields around 71%. Mechanochemical approaches using salts as catalysts enable solvent-free synthesis with comparable 60–80% yields, though these remain non-commercial.

History

Development and approval

Tolbutamide's development originated in the 1940s from research on antibiotics, which unexpectedly exhibited hypoglycemic effects in patients. French physician Marcel Janbon observed these effects in 1942 while testing the sulfonamide carbutamide for , prompting further investigation into derivatives as potential antidiabetic agents. Following , German pharmaceutical company synthesized various , including the precursor carbutamide (BZ-55), which showed promise but was withdrawn due to severe toxicity, such as granulocytopenia. Hoechst then developed a safer analog, D-860 (tolbutamide), through systematic modification of the structure to reduce side effects while retaining hypoglycemic activity. A cross-licensing agreement with the Upjohn Company facilitated its advancement in the United States. Preclinical studies in 1950 demonstrated tolbutamide's hypoglycemic effects in rabbits, confirming its potential without the of earlier compounds. trials began in 1954, involving initial assessments in small cohorts of diabetic patients, which supported progression to larger studies. filed a (NDA) with the FDA in 1956, comprising 10,580 pages across 23 volumes that included data from 5,786 patient cases documenting and . The FDA approved tolbutamide in January 1957 under the brand name Orinase for use as an adjunct to diet in managing mild mellitus. Initially marketed and as an oral alternative to insulin for non-insulin-dependent , tolbutamide achieved peak sales in the , becoming one of the most prescribed antidiabetic agents worldwide. Its patents, including US Patent 2,968,158 held by , expired in the 1970s, enabling the introduction of generic versions and broader accessibility.

Clinical studies and controversies

The University Group Diabetes Program (UGDP), a multicenter conducted from 1960 to 1970 involving over 1,000 patients with , evaluated the long-term effects of oral hypoglycemic agents on vascular complications. In the tolbutamide arm (1.5 g daily plus diet), the cardiovascular mortality rate was approximately 2.5 times higher than in the (diet-only) group after 5–8 years of follow-up, with 26 cardiovascular deaths in the tolbutamide group (n=205) versus 10 in (n=204), corresponding to rates of about 25 and 12 per 1,000 patient-years, respectively. The UGDP findings sparked significant controversy, with critics highlighting flaws in study design, including inconsistent glucose measurement methods across sites, lack of blinding, variable patient adherence, and the fact that mortality was not a predefined primary endpoint, leading to concerns over data interpretation and potential bias. Despite these debates, the FDA responded in 1970 by requiring a on tolbutamide and other about the potential increased risk of cardiovascular mortality, though the drug was not withdrawn from the market. Subsequent large-scale trials provided contrasting evidence, alleviating some concerns about sulfonylureas as a class. The Prospective Diabetes Study (UKPDS, 1998), involving 3,867 patients with newly diagnosed , found no excess cardiovascular risk with therapy (primarily second-generation agents like gliclazide and glibenclamide) compared to insulin, and tolbutamide served as a historical comparator in analyses showing similar overall safety profiles for the drug class. Tolbutamide's use in intravenous diagnostic testing for prediabetes and insulinomas also led to serious issues, as the test provoked severe hypoglycemic reactions, including fatal events in some non-diabetic or prediabetic individuals, prompting its abandonment in the 1970s due to safety risks. These developments contributed to a clinical shift toward second-generation sulfonylureas (e.g., glipizide, glyburide), which offered improved pharmacokinetics and lower hypoglycemia risk, leading to tolbutamide's phase-out in routine practice by the early 2000s; it was discontinued in the US market around 2002.

Society and culture

Brand names and formulations

Tolbutamide has been marketed under various brand names globally, primarily as an oral antidiabetic agent. The original and primary brand name was Orinase, developed and produced by The Upjohn Company (later acquired by ), formulated as 500 mg scored, immediate-release tablets for . Other notable international brands include Rastinon, marketed by Hoechst (now part of ), which is available in similar tablet forms in multiple countries. Generic versions, such as Tol-Tab and Dirastan, have also been distributed under various labels. Tolbutamide is exclusively available in immediate-release oral tablet formulations, typically in strengths of 500 mg or 1 g, with no extended-release, injectable, or other approved or marketed. A specialized product, Orinase Diagnostic (sodium tolbutamide for intravenous use in diagnostic testing), was once available but has been discontinued. In terms of availability, tolbutamide under brand names like Orinase was discontinued in the United States around 2000, with limited generic options remaining thereafter. However, generic formulations continue to be common and accessible in developing countries, such as and parts of , where cost-effective antidiabetic therapies are in demand. In the , tolbutamide is classified as a prescription-only and is not subject to any DEA scheduling requirements. It received FDA approval for the management of mellitus, but the branded version, Orinase, produced by , was discontinued in 2000 due to declining demand and the availability of newer therapies. Commercial formulations are no longer available, though the drug can be prepared through compounding pharmacies for specific patient needs. Internationally, tolbutamide appears on the World Health Organization's Model List of (23rd list, 2023) as a core agent for , reflecting its historical role in accessible care. In the , it remains available by prescription only, with regulatory oversight ensuring appropriate use. Generic versions are widely accessible by prescription in developing countries such as , facilitating low-cost treatment in resource-limited areas. Tolbutamide's market withdrawal stems primarily from its replacement by second-generation and other antidiabetic drugs with improved safety profiles and fewer cardiovascular concerns, as highlighted in historical studies like the University Group Diabetes Program. No active recalls have been issued for tolbutamide, but ongoing monitoring for allergies is recommended due to its . Access challenges include occasional shortages in developed markets driven by low demand and manufacturing discontinuation. As a , tolbutamide remains inexpensive, with costs typically ranging from approximately $0.10 to $0.71 per 500 mg tablet depending on sourcing and quantity. As of 2025, its clinical use is limited primarily to niche applications in research.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Tolbutamide
  2. https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682481.html
  3. https://pubmed.ncbi.nlm.nih.gov/6781341/
  4. https://www.ncbi.nlm.nih.gov/books/NBK548841/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC4366767/
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC6304295/
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC3714066/
  8. https://www.ncbi.nlm.nih.gov/books/NBK501119/
  9. https://medlineplus.gov/druginfo/meds/a682481.html
  10. https://go.drugbank.com/drugs/DB01124
  11. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/565513
  12. https://diabetesjournals.org/care/article/38/1/170/37779/Should-Sulfonylureas-Remain-an-Acceptable-First
  13. https://jamanetwork.com/journals/jama/fullarticle/324072
  14. https://www.drugs.com/pro/tolbutamide.html
  15. https://www.drugs.com/dosage/tolbutamide.html
  16. https://www.mayoclinic.org/drugs-supplements/tolbutamide-oral-route/proper-use/drg-20072031
  17. https://www.ncbi.nlm.nih.gov/books/NBK513225/
  18. https://diabetesjournals.org/diabetes/article/51/suppl_3/S368/13148/Sulfonylurea-Stimulation-of-Insulin-Secretion
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC3806600/
  20. https://s3.pgkb.org/attachment/Tolbutamide_05_20_19_FDA.pdf
  21. https://pubmed.ncbi.nlm.nih.gov/6147291/
  22. https://diabetesjournals.org/books/book/47/chapter/5111054/Sulfonylureas
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC5956062/
  24. https://pubmed.ncbi.nlm.nih.gov/12648023/
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC2930813/
  26. https://pubmed.ncbi.nlm.nih.gov/11875364/
  27. https://pubmed.ncbi.nlm.nih.gov/10681382/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC2014169/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC5393509/
  30. https://www.drugs.com/sfx/tolbutamide-side-effects.html
  31. https://www.aapharma.ca/downloads/en/PIL/2016/Tolbutamide-PI.pdf
  32. https://www.acpjournals.org/doi/10.7326/0003-4819-53-1-194
  33. https://www.sciencedirect.com/topics/chemistry/tolbutamide
  34. https://www.sciencedirect.com/topics/medicine-and-dentistry/tolbutamide
  35. https://www.aaaai.org/allergist-resources/ask-the-expert/answers/2023/sulfonamide
  36. https://www.glowm.com/resources/glowm/cd/pages/drugs/t040.html
  37. https://pubmed.ncbi.nlm.nih.gov/15467178/
  38. https://jamanetwork.com/journals/jama/fullarticle/345680
  39. https://diabetesjournals.org/care/article/40/5/706/36863/Sulfonylureas-and-the-Risks-of-Cardiovascular
  40. https://www.mims.com/philippines/drug/info/tolbutamide?mtype=generic
  41. https://pubmed.ncbi.nlm.nih.gov/10725317/
  42. https://pubmed.ncbi.nlm.nih.gov/7450929/
  43. https://pubmed.ncbi.nlm.nih.gov/1233266/
  44. https://journals.sagepub.com/doi/10.1177/003591576505811P202
  45. https://www.amjmed.com/article/0002-9343%2886%2990933-2/abstract
  46. https://australianprescriber.tg.org.au/articles/drug-interactions-with-oral-hypoglycaemic-drugs.html
  47. https://www.rxfiles.ca/rxfiles/uploads/documents/diabetes-QandA-Hypoglycemic-DIs.pdf
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC6761694/
  49. https://www.bmj.com/content/351/bmj.h6223
  50. https://webbook.nist.gov/cgi/inchi?ID=C64777&Mask=4
  51. https://www.chemspider.com/Chemical-Structure.5304.html
  52. https://www.chemicalbook.com/ProductChemicalPropertiesCB4709039_EN.htm
  53. https://www.caymanchem.com/product/19888/tolbutamide
  54. https://etd.ohiolink.edu/acprod/odb_etd/ws/send_file/send?accession=toledo1271439418&disposition=inline
  55. https://patents.google.com/patent/US2968158A/en
  56. https://www.chemicalbook.com/synthesis/tolbutamide.htm
  57. https://pubs.rsc.org/en/content/articlepdf/2024/mr/d4mr00031e
  58. https://www.wjpps.com/Wjpps_controller/abstract_id/12314
  59. https://pubmed.ncbi.nlm.nih.gov/1794272/
  60. https://karger.com/books/book/2152/chapter/5708171/Historical-Development-of-Oral-Antidiabetic-Agents
  61. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/tolbutamide
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC6909290/
  63. https://diabetesjournals.org/diabetes/article/19/11/785/4581/A-Study-of-the-Effects-of-Hypoglycemic-Agents-on
  64. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)07019-6/fulltext
  65. https://journals.co.za/doi/pdf/10.10520/AJA20785135_34363
  66. https://reference.medscape.com/drug/tolbutamide-342725
  67. https://www.rxlist.com/tolinase-drug.htm
  68. https://www.linkedin.com/pulse/tolbutamide-cas-64-77-7-market-opportunities-landscape-feurf
  69. https://www.goodrx.com/tolbutamide/what-is
  70. https://list.essentialmeds.org/recommendations/1035
  71. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02
  72. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020496s028lbl.pdf
  73. https://www.pharmacychecker.com/tolbutamide/
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