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1.
Comp Biochem Physiol C Toxicol Pharmacol ; 133(4): 587-92, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12458186

ABSTRACT

The pharmacokinetic profile of S(-)-hydroxyhexamide (S-HH), a pharmacologically active metabolite of acetohexamide, was examined in male and female rats. S-HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S-HH in rats. Testectomy caused significant alteration in these parameters of S-HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL(p)) of S-HH in male rats, but had no effect in the females. The plasma concentrations of acetohexamide generated from S-HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S-HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S-HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome p450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.


Subject(s)
Acetohexamide/analogs & derivatives , Acetohexamide/metabolism , Acetohexamide/pharmacokinetics , Sex Characteristics , Acetohexamide/administration & dosage , Acetohexamide/blood , Animals , Female , Male , Rats , Rats, Wistar
2.
Life Sci ; 69(16): 1947-55, 2001 Sep 07.
Article in English | MEDLINE | ID: mdl-11693275

ABSTRACT

A short-lasting hypoglycemic effect was observed when S(-)-hydroxyhexamide (S-HH), a major metabolite of acetohexamide, and its enantiomer R(+)-hydroxyhexamide (R-HH), were administered orally to rats. Since the reductive metabolism of acetohexamide is known to be reversible in rats, oral administration of R-HH may exhibit the hypoglycemic effect through the generation of acetohexamide. However, oral administration of R-HH to rabbits, in spite of their inability to oxidize R-HH to acetohexamide, caused a significant decrease and increase, respectively, of plasma glucose and insulin levels. Furthermore, both S-HH and R-HH were found to stimulate the secretion of insulin from hamster HIT T15 cells (pancreatic beta-cells). These results provide further evidence that both R-HH and S-HH exhibit a significant hypoglycemic effect.


Subject(s)
Acetohexamide/analogs & derivatives , Acetohexamide/pharmacology , Hypoglycemic Agents/pharmacology , Acetohexamide/administration & dosage , Acetohexamide/metabolism , Administration, Oral , Animals , Blood Glucose/drug effects , Cricetinae , Dose-Response Relationship, Drug , Hypoglycemic Agents/administration & dosage , Insulin/analysis , Insulin/blood , Islets of Langerhans/cytology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Male , Rabbits , Rats , Rats, Wistar , Stereoisomerism , Time Factors
3.
Eur J Pharmacol ; 389(2-3): 253-6, 2000 Feb 18.
Article in English | MEDLINE | ID: mdl-10688991

ABSTRACT

We investigated the mechanism of the hypoglycemic effect of (R)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)benzene-sulfonamide [(R)-acetoxyhexamide; (R)-ACX], a new sulfonylurea compound. (R)-ACX potently stimulated the release of insulin from cultured pancreatic beta-cells (HIT T15 cells), established from hamster islet cells SV40-transformed. When (R)-ACX was orally administered to fasted rats, it decreased the plasma glucose level in a dose-dependent manner. The hypoglycemic effect of (R)-ACX was quick and short lasting, as compared to that of acetohexamide and glibenclamide. The quick and short-lasting hypoglycemic effect of (R)-ACX was thought likely to result from rapid absorption of (R)-ACX and rapid elimination of (R)-ACX and its metabolite, (R)-hydroxyhexamide. Furthermore, (R)-ACX was found to suppress the increase of blood glucose level due to starch loading in fasted mice. (R)-ACX may be useful in the control of postprandial hyperglycemia to patients with non-insulin-dependent diabetic mellitus.


Subject(s)
Hypoglycemic Agents/pharmacology , Sulfonylurea Compounds/pharmacology , Acetohexamide/analogs & derivatives , Acetohexamide/pharmacology , Animals , Blood Glucose/analysis , Cell Line , Cricetinae , Dose-Response Relationship, Drug , Glyburide/pharmacology , Insulin/metabolism , Insulin Secretion , Male , Mice , Mice, Inbred ICR , Rats , Rats, Wistar , Sulfonylurea Compounds/metabolism
4.
Chem Pharm Bull (Tokyo) ; 47(8): 1164-6, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10478471

ABSTRACT

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%, > 99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%, > 99% ee) and unchanged (S)-2 (46%, 78% ee).


Subject(s)
Acetohexamide/analogs & derivatives , Benzamides/chemical synthesis , Lipase/chemistry , Pseudomonas/enzymology , Acetohexamide/chemical synthesis , Acetohexamide/chemistry , Acetylation , Benzamides/chemistry , Hydrolysis , Solvents , Stereoisomerism , Vinyl Compounds
5.
J Biochem ; 121(4): 705-10, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9163521

ABSTRACT

The structural requirements of acetohexamide reductases purified from rabbit liver, kidney, and heart for substrates and inhibitors were examined. Acetohexamide, an oral antidiabetic drug with a ketone group, and analogs of it with various alkyl groups instead of the cyclohexyl group were used as substrates for these three enzymes. The results obtained as to substrate specificity suggested that the nature of the substrate-binding region of the heart enzyme is markedly different from those of the substrate-binding regions of the liver and kidney enzymes. Tolbutamide, which has no ketone group within its chemical structure, strongly inhibited the heart enzyme, whereas it had little ability to inhibit the liver or kidney enzyme. The inhibition of the heart enzyme by tolbutamide was competitive with respect to acetohexamide and uncompetitive with respect to NADPH. Furthermore, tolbutamide analogs with n-pentyl and n-hexyl groups instead of the n-butyl group exhibited very pronounced inhibition of only the heart enzyme. Therefore, it is reasonable to postulate that the heart enzyme, unlike the liver and kidney ones, has a cleft of a strongly hydrophobic nature near its substrate-binding region, and that this hydrophobic cleft plays a critical role in the interaction of the heart enzyme with the cyclohexyl group of acetohexamide.


Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases/metabolism , Kidney/enzymology , Liver/enzymology , Myocardium/enzymology , Acetohexamide/analogs & derivatives , Acetohexamide/chemistry , Acetohexamide/metabolism , Animals , Binding Sites , Carbutamide/chemistry , Carbutamide/pharmacology , Chlorpropamide/chemistry , Chlorpropamide/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Kinetics , Oxidation-Reduction , Rabbits , Structure-Activity Relationship , Substrate Specificity , Tolbutamide/analogs & derivatives , Tolbutamide/metabolism , Tolbutamide/pharmacology , Triazines/chemistry , Triazines/metabolism , Triazines/pharmacology
6.
J Biochem ; 119(4): 648-52, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8743564

ABSTRACT

An enzyme catalyzing the metabolic reduction of acetohexamide [4-acetyl-N-(cyclohexyl-carbamoyl)benzenesulfonamide], an oral antidiabetic drug, was purified to homogeneity from the cytosolic fraction of rabbit heart. The molecular mass of the purified enzyme was estimated to be 110 kDa by gel filtration and nondenaturing PAGE and 28 kDa by SDS-PAGE, suggesting that the enzyme is composed of four identical-size subunits. 4-Benzoyl-pyridine and p-nitroacetophenone, typical substrates of carbonyl reductase [EC 1.1.1.184], were not reduced by the enzyme. Of drugs with a ketone group tested, only acetohexamide was a good substrate of the enzyme. the enzyme effectively reduced analogs substituted with various alkyl groups instead of the cyclohexyl group in acetohexamide, although it had little or no ability to reduce analogs substituted with various alkyl groups instead of the methyl group in acetohexamide. The enzyme was inhibited not only by quercetin, a well-known inhibitor of carbonyl reductase, but also by phenobarbital, a potent inhibitor of aldehyde reductase [EC 1.1.1.2]. These results indicate that the enzyme purified from rabbit heart is a novel enzyme responsible for the reduction of acetohexamide and its analogs.


Subject(s)
Acetohexamide/metabolism , Alcohol Oxidoreductases/isolation & purification , Alcohol Oxidoreductases/metabolism , Myocardium/enzymology , Acetohexamide/analogs & derivatives , Alcohol Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases/chemistry , Animals , Catalysis , Enzyme Inhibitors/pharmacology , Male , Molecular Weight , Phenobarbital/pharmacology , Quercetin/pharmacology , Rabbits , Substrate Specificity
7.
Biochem Mol Biol Int ; 33(5): 893-9, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7987258

ABSTRACT

A correlation was observed between the values of specificity constant (kcat/Km) of carbonyl reductase from rabbit liver for acetohexamide analogs and their partition coefficients. This result indicates that the hydrophobicity in straight-chain alkyl groups of acetohexamide analogs plays an important role in the catalytic activity and substrate-binding capacity of the enzyme. Furthermore, the double logarithmic plots of kcat/Km values of the enzyme for 4-acetylpyridine analogs with a straight-chain alkyl group up to five carbon atoms against their partition coefficients gave a straight line. On the other hand, the plots for 4-acetylpyridine analogs with a straight-chain alkyl group over five carbon atoms and with a branched-chain alkyl group were away from the straight line. It is reasonable to postulate that a hydrophobic pocket is located in the substrate-binding domain of the enzyme.


Subject(s)
Acetohexamide/analogs & derivatives , Alcohol Oxidoreductases/metabolism , Liver/enzymology , Pyridines , Alcohol Oxidoreductases/isolation & purification , Animals , Binding Sites , Catalysis , Kinetics , Rabbits , Substrate Specificity
8.
Nihon Naibunpi Gakkai Zasshi ; 67(1): 42-9, 1991 Jan 20.
Article in English | MEDLINE | ID: mdl-2013345

ABSTRACT

Prolonged hypoglycemia induced by acetohexamide (AH) in a patient with noninsulin dependent diabetes mellitus accompanied by primary hypothyroidism was presented. A 74-year-old man who had been treated with AH (500mg, daily) for diabetes mellitus since 1973 was admitted to our hospital in Oct. 1988 because of hypoglycemic coma. On admission, the level of blood glucose was 20mg/dl. Continuous intravenous administration of 10 per cent glucose solution led to improvement in the mental state on the second day. However, the level of blood glucose remained between 30 to 45mg/dl for four days after admission. On the fifth day, a fasting blood glucose level finally reached 75mg/dl. In a thyroid function test, the serum levels of thyroid hormone showed the following decreases: T3 68ng/dl, T4 2.8 micrograms/dl, free T4 0.3ng/dl, while basal TSH levels increased to 50.3 microU/ml. Since anti-thyroid microsomal antibody was positive and thyroid 99mTc-pertechnetate uptake was slightly elevated, the hypothyroidism in this patient was considered to be caused by chronic thyroiditis. Urinalysis was positive for protein. In a renal function test, the blood urea nitrogen was 26.7mg/dl and creatinine 1.7mg/dl, and creatinine clearance decreased to 22ml/min. After thyroid function returned to euthyroid, creatinine clearance improved (41 ml/min). To clarify the relationship between hypothyroidism and the metabolism of AH, the serum levels of AH and its metabolite hydroxyhexamide (HH) following oral administration of AH (500mg) were evaluated before and after thyroxine replacement therapy. The blood glucose level before therapy was lower than that after therapy, and hypoglycemic symptoms were observed early in the second and third morning after AH administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Acetohexamide/adverse effects , Hypoglycemia/chemically induced , Hypothyroidism/complications , Acetohexamide/analogs & derivatives , Acetohexamide/blood , Acetohexamide/metabolism , Aged , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Half-Life , Humans , Hypothyroidism/drug therapy , Hypothyroidism/metabolism , Male , Thyroxine/therapeutic use
9.
J Pharmacobiodyn ; 12(12): 731-5, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2699749

ABSTRACT

The stereoselective reduction of acetohexamide, an oral antidiabetic drug, was studied by using the cytosol of rabbit liver. A major metabolite of acetohexamide was isolated in 41.5% yield from the enzyme reaction mixture, and identified as (-)-hydroxyhexamide by techniques including the melting point, thin-layer chromatography, infrared spectrometry and optical rotation. The enantiomeric purity of (-)-hydroxyhexamide was determined on the basis of the proton nuclear magnetic resonance (400 MHz) spectrum of ester (diasteromer) derived by the reaction of (-)-hydroxyhexamide with (R)-(+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride. The (-)-hydroxyhexamide isolated from the enzyme reaction mixture was almost 100% in that enantiomeric form. The metabolic reduction of acetohexamide in the cytosol of rabbit liver appeared to be catalyzed by some enzymes with the same stereoselectivity.


Subject(s)
Acetohexamide/metabolism , Cytosol/metabolism , Liver/ultrastructure , Acetohexamide/analogs & derivatives , Acetohexamide/isolation & purification , Alcohol Oxidoreductases/metabolism , Animals , Chromatography, Ion Exchange , Cytosol/enzymology , Liver/enzymology , Magnetic Resonance Spectroscopy , Male , Oxidation-Reduction , Rabbits , Stereoisomerism
10.
J Pharmacobiodyn ; 12(8): 503-7, 1989 Aug.
Article in English | MEDLINE | ID: mdl-2614641

ABSTRACT

The in vivo and in vitro bindings of (-)-hydroxyhexamide, a major metabolite of acetohexamide, to rabbit serum were examined by using an ultrafiltration method. The in vivo serum protein binding of (-)-hydroxyhexamide was much lower than the in vitro serum protein binding. The in vitro serum protein binding of (-)-hydroxyhexamide was strongly displaced by the addition of acetohexamide. Furthermore, the in vitro serum protein binding of (-)-hydroxyhexamide in the presence of acetohexamide and (-)-hydroxyhexamide at the same concentrations as those found 1.0 h after acetohexamide administration was approximately similar to the in vivo serum protein binding of (-)-hydroxyhexamide. These results lead us to conclude that acetohexamide, the parent drug of (-)-hydroxyhexamide, plays an important role in the in vivo serum protein binding of (-)-hydroxyhexamide.


Subject(s)
Acetohexamide/analogs & derivatives , Acetohexamide/metabolism , Blood Proteins/metabolism , Acetohexamide/blood , Acetohexamide/isolation & purification , Acetohexamide/pharmacokinetics , Animals , Binding, Competitive , In Vitro Techniques , Male , Protein Binding , Rabbits
11.
J Pharm Pharmacol ; 41(4): 227-30, 1989 Apr.
Article in English | MEDLINE | ID: mdl-2568460

ABSTRACT

Infrared data determined for known polymorphic forms and some new derivatives of acetohexamide and related compounds support the view that acetohexamide polymorphs exhibit keto-enol tautomerism. They indicate that type A polymorphs exist in the enol form, probably stabilized by intramolecular bonding between an O-H and S = O group to form a six-membered ring. Type B polymorphs exist in the keto form with the urea carbonyl group intermolecularly bonded to a sulphonamide N-H. The new evidence disputes previous interpretations of the data.


Subject(s)
Acetohexamide/analysis , Acetohexamide/analogs & derivatives , Chlorpropamide/analysis , Crystallization , Spectrophotometry, Infrared , Stereoisomerism , Tolbutamide/analysis , X-Ray Diffraction
12.
Chem Pharm Bull (Tokyo) ; 37(3): 760-5, 1989 Mar.
Article in English | MEDLINE | ID: mdl-2752490

ABSTRACT

The pharmacokinetic profiles of the hypoglycemic agent, acetohexamide (AH) and its major active metabolite, hydroxyhexamide (HH) were studied in three species of laboratory animals after intraperitoneal (ipl) administration in comparison with those after intravenous (iv) administration of AH and of the preformed metabolite HH. Reductive biotransformation of AH to HH was reversible in rats and guinea pigs, while it was irreversible in rabbits. The parameters of reversible drug-metabolite pharmacokinetics were calculated, including essential clearances of reversible and irreversible elimination, volumes of distribution at the steady state and sojourn times or turnover rates of the metabolite pair. An interconversion model, which incorporated a first-pass metabolism, was applied to the disposition kinetics of AH and HH, and the available fractions of AH and generated metabolite HH in each species were elucidated.


Subject(s)
Acetohexamide/analogs & derivatives , Acetohexamide/pharmacokinetics , Acetohexamide/metabolism , Animals , Guinea Pigs , Injections, Intraperitoneal , Injections, Intravenous , Male , Rabbits , Rats , Rats, Inbred Strains
14.
J Pharmacobiodyn ; 11(5): 309-13, 1988 May.
Article in English | MEDLINE | ID: mdl-2971793

ABSTRACT

The acetohexamide reductase activity in 10000 x g supernatant fluids of kidney homogenates was significantly higher in male than in female rats. Although difference in activity of acetohexamide reductase in the cytosol between the sexes was not observed, the activity in the microsomes was considerably higher in male than in female rats. These findings indicate that the microsomal enzyme plays an important role in the sex difference of acetohexamide reduction by 10000 x g supernatant fluids of kidney homogenates. The sensitivities to inhibitors of microsomal acetohexamide reductase were different from those of cytosolic acetohexamide reductase. Furthermore, streptozotocin-induced diabetes significantly decreased acetohexamide reductase activity only in the kidney microsomes of male rats, resulting in the abolishment of the sex difference of acetohexamide reduction by 10000 x g supernatant fluids of kidney homogenates.


Subject(s)
Acetohexamide/metabolism , Diabetes Mellitus, Experimental/metabolism , Kidney/metabolism , Acetohexamide/analogs & derivatives , Acetohexamide/analysis , Animals , Female , Male , Oxidation-Reduction , Rats , Rats, Inbred Strains , Sex Factors , Streptozocin/toxicity , Subcellular Fractions/analysis
17.
Biomed Mass Spectrom ; 5(2): 123-7, 1978 Feb.
Article in English | MEDLINE | ID: mdl-630049

ABSTRACT

Some confusion has arisen in the literature regarding the electron impact mass spectrum of N-methyltolbutamide. The situation is complicated by the thermal lability of this compound which causes the formation of the corresponding N-methylsulfonamide. We present here spectral data at relatively low probe temperatures (and without an intervening gas chromatographic system) which we believe define the mass spectrum of N-methyltolbutamide more accurately than before. Similar data are presented for the analogous N-methylacetohexamide and show a rearrangement process for both substances not reported previously for this class of compounds.


Subject(s)
Sulfonylurea Compounds , Acetohexamide/analogs & derivatives , Mass Spectrometry/methods , Tolbutamide/analogs & derivatives
19.
J Pharm Sci ; 66(5): 635-8, 1977 May.
Article in English | MEDLINE | ID: mdl-874743

ABSTRACT

A sensitive and specific GLC assay was developed for acetohexamide and hydroxyhexamide, its major metabolite, in plasma and urine. The assay uses tolbutamide as a mass internal standard. Compounds are extracted from acidified plasma or urine with toluene, converted to methylated derivatives with dimethyl sulfate, and measured by GLC using a flame-ionization detector. With GLC-mass spectrometry, the compounds measured are the N-methylsulfonamides resulting from GLC pyrolysis. Plasma and urine data are presented from a bioavailability study to demonstrate the utility of this method.


Subject(s)
Acetohexamide/analogs & derivatives , Acetohexamide/analysis , Acetohexamide/blood , Acetohexamide/urine , Biological Availability , Blood Glucose/analysis , Chromatography, Gas , Humans , Insulin/blood , Mass Spectrometry , Methods , Tablets , Time Factors
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