Acetohexamide dosing

Following oral administration of 750 mg of three different tablet formulations to 8 subjects, mean peak plasma-acetohexamide concentrations of about 28, 40, and 44 ig/ml were attained 2 hours after a dose mean peak plasma concentrations of ( —)-l-hydroxyhexamide averaged about 30 i.g/ml (J. W. Kleberer o/., J. pharm. Sci., 1977, 66, 635-638). After daily oral doses of 0.5 g to 18 subjects, an average serum concentration of 42 pg/ml was reported 3 to 5 hours after the dose (J. Sheldon er a/.. Diabetes, 1965,14, 362-367). 

No pharmacokinetic studies have been reported in the literature. However, seventy to eighty percent of a single oral dose of 1 gram of acetohexamide was recovered as a metabolite within 24 hours in the urine of four human volunteers. It is suggested that acetohexamide is converted to hydroxyhexamide in the liver. Acetohexamide and hydroxyhexamide are probably converted to hydroxyacetohexamide and hydroxyhydroxyhexamide in both the liver and kidneys9. 

Acetohexamide (active metabolite, -l dose in renal dysfunction)... 

Acetohexamide (Dymelor) 12-24 (1 -5)c Average dose 1,000 mg L-(-)-hydroxy-metabolite... 

The first-generation sulfonylureas vary considerably in their half-lives and extents of metabo-hsm. The tj of acetohexamide is short, but it is reduced to an active compound whose tj is similar to those of tolbutamide and tolazamide (4-7 hours). These drugs may require divided daily doses. Chlorpropamide has a long (24-48 hours). The second-generation agents are approximately... 

Acetohexamide Is largely metabolized to an active metabolite which Is excreted In the urine (see below). Therefore, dosage adjustment or total avoidance Is necessary In certain cases. One such case Is the renal failure. Azotenic patients may experience prolonged hypoglycemia. A twice dally dose Is recommended for patients with mild renal failure and patients with moderate to severe renal failure should not receive the drug (38,39). 

Orally administered acetohexamide is almost completely absorbed (47). It is reported to appear in the blood within 30 minutes after PO administration and peak levels occur after 3 to 5 hours (43,44). Galloway et a1. (45) reported that, following single PO doses of 1 g of acetohexamide, mean peak blood levels of the drug to be 47 mcg/ml and for hydroxyhexamide mean levels of 60.3 mcg/ml were achieved. These peak levels occurred within 1.5 to 2 hours for the parent compound versus 2 to 6 hours for the active metabolite, hydroxyhexamide. 

Acetohexamide and Its metabolites are mainly excreted by the kidneys. The urinary recovery of radioactivity after the administration of oral i4c-iabe1ed acetohexamide averaged 71.6X In 24 hours (45). Approximatley one-half to two-third of the drug was reported to be excreted In urine as the active metabolite, hydroxyhexamide (45,50). Fecal excretion of radioactivity following oral administration of the drug 1n one patient was 15X. Even after 1 g I.V. dose urinary recovery was only 85X (45), suggesting that biliary excretion represents a secondary route of elimination of acetohexamide and/or Its metabolites. However, more data are needed to confirm the occurrence of biliary excretion. 

A long-term study in 53 patients with type 2 diabetes found that chlorothiazide 500 mg or 1 g daily or trichlormethiazide 4 or 8 mg daily caused a mean rise in blood glucose levels from about 6.7 to 7.8 mmol/L. Only 7 patients needed a change in their treatment 4 required more of their ord antidiabetic, 2 an increase in insulin dose, and one was transferred from tolbutamide to insulin. The oral antidiabetics used included toibutamide, chlorpropamide, acetohexamide and phenformin. ... 

Diabetes and asthma are seldom found together in the same patient. In one case with diabetes, nasal polyps, asthma and aspirin sensitivity, the asthma was difficult to control and required increasing doses of corticosteroid until insulin was stopped and the diabetes controlled (albeit poorly) with oral acetohexamide (51 ). 

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