Absorption, Distribution and Excretion
Rapidly absorbed from the GI tract.
ACETOHEXAMIDE IS RAPIDLY ABSORBED, & MAX HYPOGLYCEMIC ACTIVITY IS OBSERVED ABOUT 3 HR AFTER INGESTION. TOTAL DURATION OF ACTION IS 12-24 HR. MUCH OF ACTIVITY IS ASCRIBABLE TO METABOLITE, HYDROXYHEXAMIDE, WHICH HAS PLASMA T/2 OF ABOUT 6 HR...ACETOHEXAMIDE, HAS PLASMA T/2 OF 1.3 HR.
IN PERSONS WITH NORMAL RENAL & HEPATIC FUNCTION, MORE THAN 80% IS EXCRETED, LARGELY AS METABOLITES, IN 24 HR.
TIME OF PEAK CONCN AFTER ORAL DOSE: 3 HR /FROM TABLE/
...5 DAYS AFTER ORAL DOSE...TO RATS. 86% WAS EXCRETED IN 24-HR URINE & 9% IN 48-HR FECES. RESULTS INDICATED RAPID ABSORPTION & EXCRETION...
For more Absorption, Distribution and Excretion (Complete) data for ACETOHEXAMIDE (8 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Extensively metabolized in the liver to the active metabolite hydroxyhexamide, which exhibits greater hypoglycemic potency than acetohexamide. Hydroxyhexamide is believed to be responsible for prolonged hypoglycemic effects.
HYDROXYHEXAMIDE...MAJOR METABOLITE OF ACETOHEXAMIDE...IN HUMANS, HAS L-CONFIGURATION. ...CONTRIBUTES SIGNIFICANTLY TO HYPOGLYCEMIC RESPONSE THAT FOLLOWS ADMIN...
PRINCIPAL ROUTE OF METABOLIC DEGRADATION IN MAN...REDUCTION OF P-ACETYL GROUP TO /1-[(P-ALPHA-HYDROXYETHYLBENZENE)SULFONYL]-3-CYCLOHEXYLUREA WHICH/ EXHIBITS HYPOGLYCEMIA IN MAN & OTHER ANIMALS. &...MAY PROLONG HYPOGLYCEMIC ACTIVITY OF ACETOHEXAMIDE /ORAL/
Sulfonylureas are rapidly absorbed from the gastrointestinal tract, transported in the blood in highly protein-bound complexes, and subjected to extensive hepatic metabolism (except for chlorpropamide). Wide variation exists among the sulfonylureas in hepatic metabolism and remnal clearance, factors that tend to alter the steady-state serum levels. Metabolites may be active, so there may be a variation between the plasma half-life of the parent drug and the degree of hypoglycemia encountered. /Sulfonylurea/
Active metabolite greater than parent drug. Metabolite excreted, in part, by kidney. /from table/

---

Biological Half-Life
Elimination half-life of the parent compound is 1.3 hours and the elimination half-life of the active metabolite is approximately 5-6 hours.
Half-life...3.5-11 /hours/ /from table/

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Acetohexamide is no longer marketed in the United States. Because no information is available on the use of acetohexamide during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with hypoglycemic agents.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
90%

---

Interactions
DRUGS THAT MAY INCR RISK OF HYPOGLYCEMIA FROM SULFONYLUREAS INCL OTHER HYPOGLYCEMIC AGENTS, SULFONAMIDES, PROPRANOLOL, SALICYLATES, PHENYLBUTAZONE, PROBENECID, DICUMAROL, CHLORAMPHENICOL, MONOAMINE OXIDASE INHIBITORS, & ALCOHOL. /SULFONYLUREAS/
IN DIABETIC PT WITHOUT HEPATIC OR RENAL IMPAIRMENT, PLASMA HALF-LIFE...WAS NOT CHANGED BY CONCURRENT TREATMENT WITH PHENYLBUTAZONE, BUT THERE WAS CONSIDERABLE PROLONGATION OF HALF-LIFE OF ITS METABOLITE, HYDROXYHEXAMIDE, WHICH IS ALSO AN EFFECTIVE HYPOGLYCEMIC AGENT.
DAILY INGESTION ACETOHEXAMIDE (100 MG/KG) & PHENFORMIN (50 MG/KG) 7 DAYS WITH IP DIPHENYLHYDANTOIN RESTORED THIAMINE CONTENT.
CONCOMITANT ADMIN OF SALICYLIC ACID (20 MG/KG) WITH ACETOHEXAMIDE (30 MG/KG) IV TO DOGS INCR RENAL CLEARANCE OF METABOLITE HYDROXYHEXAMIDE.
For more Interactions (Complete) data for ACETOHEXAMIDE (19 total), please visit the HSDB record page.

Acetohexamide is a white fluffy crystalline powder with almost no odor. (NTP, 1992)
Acetohexamide is an N-sulfonylurea that is urea in which a hydrogen attached to one of the nitrogens is replaced by a p-acetylphenylsulfonyl group, while a hydrogen attached to the other nitrogen is replaced by a cyclohexyl group. It has a role as a hypoglycemic agent and an insulin secretagogue. It is a N-sulfonylurea and a member of acetophenones.
A sulfonylurea hypoglycemic agent that is metabolized in the liver to 1-hydrohexamide. Acetohexamide has been discontinued in the US market.
Acetohexamide is an intermediate-acting, first-generation sulfonylurea with hypoglycemic activity. Acetohexamide is metabolized in the liver to its active metabolite hydroxyhexamide.
A sulfonylurea hypoglycemic agent that is metabolized in the liver to 1-hydrohexamide.

---

Drug Indication
Used in the management of diabetes mellitus type 2 (adult-onset).

---

Mechanism of Action
Sulfonylureas such as acetohexamide bind to an ATP-dependent K⁺ channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca²⁺ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.
SULFONYLUREAS STIMULATE ISLET TISSUE TO SECRETE INSULIN. ... ADMIN OF SULFONYLUREAS INCR CONCN OF INSULIN IN PANCREATIC REIN... /SULFONYLUREAS/
Sulfonylureas are now...thought to act by a number of different mechanisms. 1. ...produce a depolarization of the pancreatic islet beta cell membrane potassium ion permeability. This results in a release of preformed insulin into the circulation and occurs mostly in non-insulin dependent diabetics. 2. ...reduce basal glucose output from the liver... 3. increase insulin receptor binding... 4. ...increasing intracellular levels of AMP... 5. increase insulin secretion by suppressing the release of glucagon and somatostatin from alpha and delta pancreatic cells. /Sulfonylureas/
Sulfonylureas lower blood glucose in 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 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. Insulin is a hormone that lowers blood glucose and controls the storage and metabolism of carbohydrates, proteins, and fats. Therefore, sulfonylureas are effective only in patients whose pancreata are capable of producing insulin. /Sulfonylurea antidiabetic agents/

---

Therapeutic Uses
Hypoglycemic Agents
...USED IN TREATMENT OF MILD TO MODERATELY SEVERE DIABETES MELLITUS OF MATURITY-ONSET, NONKETOTIC TYPE IN PT IN WHOM DIET ALONE CANNOT CONTROL GLYCOSURIA.
...MAY BE USEFUL IN PT WHO ARE ALLERGIC TO INSULIN & ARE UNWILLING OR UNABLE TO UNDERGO DESENSITIZATION OR...TO INJECT INSULIN. ...ESP USEFUL IN ELDERLY DIABETIC WITH POOR VISION WHO LIVES ALONE & IS IN DANGER OF DEVELOPING HYPOGLYCEMIA FROM INCORRECT INSULIN DOSAGE. /ORAL HYPOGLYCEMIC AGENTS/
...IT IS ONLY ONE WITH URICOSURIC PROPERTIES, SOME CLINICIANS PREFER THIS AGENT FOR DIABETIC WITH GOUT.
For more Therapeutic Uses (Complete) data for ACETOHEXAMIDE (6 total), please visit the HSDB record page.

---

Drug Warnings
HEMATOLOGICAL (LEUKOPENIA, AGRANULOCYTOSIS, THROMBOCYTOPENIA, PANCYTOPENIA, & HEMOLYTIC ANEMIA), CUTANEOUS (RASHES, PHOTOSENSITIVITY), GI (NAUSEA, VOMITING, RARELY HEMORRHAGE), & HEPATIC (INCR SERUM ALKALINE PHOSPHATASE, CHOLESTATIC JAUNDICE) REACTIONS HAVE BEEN REPORTED.
INCIDENCE OF UNTOWARD EFFECTS IS LOW & REACTIONS ARE REVERSIBLE WHEN...DISCONTINUED.
IT IS INEFFECTIVE IN JUVENILE-ONSET, UNSTABLE, OR BRITTLE DIABETES & IS CONTRAINDICATED IN DIABETES COMPLICATED BY ACIDOSIS, KETOSIS, SEVERE INFECTIONS, COMA, SEVERE TRAUMA, OR MAJOR SURGERY.
Caution in elderly and patients with renal disease. Significant uricosuric effects. /from table/
For more Drug Warnings (Complete) data for ACETOHEXAMIDE (17 total), please visit the HSDB record page.

---

Pharmacodynamics
Acetohexamide is an intermediate-acting, first-generation oral sulfonylurea. It lowers blood sugar by stimulating the pancreatic beta cells to secrete insulin and by helping the body use insulin efficiently. Due to its primary action on the pancreatic beta cells, the drug is only effective when there are functional pancreatic beta cells that can produce insulin granules. Acetohexamide has one-third the potency of chlorpropamide, and twice the potency of tolbutamide; however, similar hypoglycemic efficacy occurs with equipotent dosage of sulfonylureas.

C15H20N2O4S

324.4

324.114

968-81-0

1989

White to off-white solid powder

1.3g/cm3

188-190° (GB 912789); mp 175-177° (Marshall)

1.581

4.072

2

4

4

22

498

0

VGZSUPCWNCWDAN-UHFFFAOYSA-N

InChI=1S/C15H20N2O4S/c1-11(18)12-7-9-14(10-8-12)22(20,21)17-15(19)16-13-5-3-2-4-6-13/h7-10,13H,2-6H2,1H3,(H2,16,17,19)

1-(4-acetylphenyl)sulfonyl-3-cyclohexylurea

Acetohexamide Dymelor Dimelin DimelorAcetohexamidGamadiabet

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~77.07 mM)

Solubility in Formulation 1: 2.5 mg/mL (7.71 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (7.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)