Tolbutamide
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Trade names | Orinase |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682481 |
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Routes of administration | Oral (tablet) |
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Pharmacokinetic data | |
Protein binding | 96% |
Metabolism | Hepatic (CYP2C19-mediated) |
Elimination half-life | 4.5 to 6.5 hours |
Excretion | Renal |
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JSmol) | |
Melting point | 128.5 to 129.5 °C (263.3 to 265.1 °F) |
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Tolbutamide is a first-generation
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
- Hypoglycemia
- Weight gain
- Hypersensitivity: cross-allergicity with sulfonamides
- Drug interactions (especially first-generation drugs): Increased hypoglycemia with 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
Orinase was developed by
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
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
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
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
References
- ISBN 978-94-009-2659-2.
- PMID 26392882.
- ^ ISBN 978-0-8018-8477-1.
- ^ Lawrence WL (24 February 1957). "Science in Review: Drug for the Treatment of Diabetes Tested And Found of Great Importance". The New York Times.
- PMID 11832527.