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PubMed1998

Population-based modeling to demonstrate extrapancreatic effects of tolbutamide.

Tolbutamide is used increasingly as an investigative tool in in vivo studies of the physiology of glucose tolerance. Its hypoglycemic effect in nondiabetic subjects is widely variable, reflecting possible variability in its pharmacokinetics, an insulinergic response, an extrapancreatic effect of the drug, or the hypoglycemic effect of insulin itself. Using population-based modeling, we have investigated the kinetics and dynamics of tolbutamide and assessed covariates in two groups of healthy subjects. The results indicate a high variability in insulinergic effect, measured by the area under of the curve of insulin (0-60 min), in response to tolbutamide injection (coefficient of variation = 29-96%). However, it appears that impaired insulin sensitivity is compensated by higher insulin secretion in response to tolbutamide. Thus the hypoglycemic effect of high insulin secretion is minimal in insulin-resistant subjects. Application of the model indicated that tolbutamide has appreciable extrapancreatic effects mediated by prolongation of the residence time of insulin in a remote effect and by enhancement of glucose effectiveness. An effect in increasing the insulin sensitivity index is also possible but could not be confirmed statistically for all groups of subjects studied. These observations may explain inconsistencies between the results of tolbutamide and insulin injection in the frequently sampled intravenous glucose tolerance test and call for further study of insulin- vs. tolbutamide-modified frequently sampled intravenous glucose tolerance tests in the assessment of the insulin sensitivity and glucose effectiveness indexes.

C-Peptide↗
PubMed1979

Secretion of glucagon and insulin in hypophysectomized rats: effect of tolbutamide.

Normal and hypophysectomized (hypox) rats, fed ad libitum, received intraperitoneal injections of tolbutamide (75 mg/kg/day) or of saline for 6 weeks. 24 h after the last injection, blood samples were taken for glucose, insulin and glucagon determinations. In normal rats, tolbutamide treatment did not alter serum glucose, insulin and glucagon, although it suppressed the secretion of insulin and glucagon by the pancreatic islets. In hypox rats, tolbutamide decreased serum glucose and insulin, elevated serum glucagon and stimulated the secretion of glucagon, but not that of insulin by the pancreatic islets. In addition, tolbutamide treatment increased the glucagon response to arginine in normal, but not in hypox rats. The serum glucose response to arginine was decreased by tolbutamide treatment and by hypophysectomy and, thus, appeared independent of the glucagon rise or preexisting glucagon level. We conclude that tolbutamide treatment decreased the secretion of glucagon and insulin in normal rats and stimulated that of glucagon in hypox rats, perhaps because of the low levels of insulin in the serum and in the pancreas of the latter. Our results are compatible with the hypothesis that the pancreatic action of tolbutamide is influenced by the pituitary.

Animals↗
PubMed1981

The effect of tolbutamide and hepatic extraction of insulin and glucagon and hepatic glucose output in anesthetized dogs.

The effects of tolbutamide and insulin infusion on hepatic extraction of insulin and glucagon and on hepatic glucose output were compared in anesthetized dogs. The basal hepatic extraction of insulin was not significantly different in the two experiments (62 +/- 7% vs. 49 +/- 8%). The fraction of insulin extracted by the liver was not changed by either tolbutamide or insulin administration. In contrast, hepatic extraction of glucagon significantly increased from a basal value of 12 +/- 8% to 41 +/- 12% 30 min after tolbutamide, coincident with hypoglycemia and increased secretion of glucagon. The percent hepatic extraction of glucagon did not change during insulin infusion despite similar hypoglycemia and an even greater increase in the amount of glucagon reaching the liver. Tolbutamide and insulin produced a transient fall in hepatic glucose output which was associated with a significant increase in the insulin to glucagon molar ratio of the portal vein. Despite the persistence of hypoglycemia, hepatic glucose production returned to control values, and the portal venous insulin to glucagon molar ratio returned toward normal. Thus, the initial hypoglycemia after tolbutamide and insulin treatment reflects decreased hepatic glucose production, while the later effects represent increased peripheral glucose utilization. Hepatic glucose output correlated better with the portal venous insulin to glucagon molar ratio than the ratio of the hormones removed by the liver. These findings indicate that insulin and glucagon extraction by the liver are quite different and are independently regulated. Tolbutamide directly increases the fraction of glucagon removed by the liver. Because of changes in hepatic extraction after tolbutamide, increased pancreatic secretion of glucagon might not be reflected in its peripheral concentration.

Animals↗
PubMed1983

Effect of tolbutamide on insulin, glucagon, and somatostatin release from the diabetic rat pancreas with special reference to glucose concentration.

The effects of tolbutamide on insulin, glucagon, and somatostatin secretion were investigated in the isolated perfused pancreas from normal and diabetic rats under low (30 mg/dl), normal (100 mg/dl), and high (300 mg/dl) glucose conditions. In the normal rat pancreas, tolbutamide-induced insulin release was increased when the glucose concentration in the perfusion medium was increased from 30-300 mg/dl. Tolbutamide had an inhibitory effect on glucagon release at the low (30 mg/dl) glucose concentrations, although a stimulatory effect was observed under normoglycemic conditions. The total amount of somatostatin secretion above baseline during tolbutamide infusion was higher under the normal glucose than under the low glucose condition. However, further augmentation of somatostatin release was not found at the high glucose concentration. In the diabetic rat pancreas, insulin release was diminished and tolbutamide-induced somatostatin release was enhanced with increasing glucose concentrations. Glucagon release was stimulated at the normal glucose concentration, but inhibited temporarily at the high glucose concentration. The maximum somatostatin response in the early phase was significantly decreased in the diabetic pancreas under low and normal glycemic conditions, when expressed as an incremental change (percentage) above baseline. From these results, one can conclude: (1) tolbutamide has a stimulatory effect on the pancreatic D cell in both the normal and diabetic pancreas; (2) the early response of somatostatin is decreased in the diabetic pancreas, except under conditions of high glucose concentration; and (3) the pancreatic A cell response to tolbutamide was not uniform and was quite different from the response of the D cell.

Animals↗
PubMed1998

A minimum of fuel is necessary for tolbutamide to mimic the effects of glucose on electrical activity in pancreatic beta-cells.

Glucose stimulation of pancreatic beta-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K+ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (>7 mM) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K+ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse beta-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 microM) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mM glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the beta-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mM glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mM was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the beta-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K+ channels is not the only mechanism by which glucose controls electrical activity in beta-cells.

Adenosine Triphosphate↗
PubMed1995

The effects of the serotonin1A receptor agonist buspirone on tolbutamide-induced hypoglycemia in rats.

The effects of the serotonin1A(5-HT1A) receptor agonist buspirone on hypoglycemia elicited by tolbutamide were investigated in rats. Buspirone, at doses not affecting plasma glucose levels, inhibited the hypoglycemic effects of tolbutamide. The inhibitory effects of buspirone on tolbutamide-induced hypoglycemia were antagonized by the 5-HT1A receptor antagonist pindolol. As tolbutamide is known to induce hypoglycemia by facilitating insulin release, the effects of buspirone on a tolbutamide-induced increase in serum insulin levels were also studied. However, buspirone did not affect tolbutamide-induced insulin release. Adrenodemedullation inhibited the effects of buspirone. These results suggest that buspirone inhibits tolbutamide-induced hypoglycemia mediated by the 5-HT1A receptor, and adrenaline release may be involved in the effects of buspirone.

Animals↗
PubMed1985

Displacing effects of chenodeoxycholic acid, ursodeoxycholic acid and sulfadimethoxine on plasma protein binding of tolbutamide.

The interactions between chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) and tolbutamide including its displacement from plasma protein binding sites were investigated pharmacokinetically. An increasing concentration of unbound tolbutamide was observed in the in vitro experiment, conducted by equilibrium dialysis method at 30 degrees C after the addition of CDCA and UDCA to human serum albumin (HSA), bovine serum albumin (BSA) and rabbit plasma containing tolbutamide. Small changes in total plasma concentration of tolbutamide were noted after high dose (0.167 mg/kg/min) intravenous infusion of CDCA to rabbits receiving a constant intravenous infusion of tolbutamide, but, such an observation was not obtained with low dose (0.083 mg/kg/min) of CDCA or with either high or low dose of UDCA. These results seem to indicate the displacement of high doses of CDCA. The coadministration of sulfadimethoxine which not only displaces tolbutamide from binding sites but also inhibits its metabolism was investigated. A different plasma pattern was obtained under the same intravenous infusion conditions, as compared with the plasma pattern resulting from tolbutamide-CDCA or UDCA combination.

Animals↗
PubMed1982

Effects of pancreatectomy, tolbutamide and insulin on glucose fluxes in chickens.

The effects of pancreatectomy and of injection of insulin or Tolbutamide on glucose fluxes in chickens were examined. This was prompted by earlier observations that Tolbutamide seems not to require the presence of pancreatic insulin for its acute hypoglycaemic action in this species. Rates of appearance (Ra) and disappearance (Rd) of glucose were estimated by isotope dilution using [14C]glucose in single-injection experiments and [14C]glucose and [6-3H]glucose in priming-injection + constant-infusion experiments. Six hours after sub-total pancreatectomy (splenic lobe remained in situ), chickens were hyperglycaemic (16.7 v. 10-4 mmol glucose/1 in controls), had a larger sampled glucose pool (4.41 v. 3.10 mmol) and a higher average rate of glucose utilization (41.7 v. 33.3 micron mol/kg per min) than sham-operated controls as estimated in single-injection experiments. Tolbutamide (50 mg/kg injected i.v.) reduced Ra in intact chickens from 33.9 to 1.1 micro mol/kg per min and reduced Ra in pancreatectomized chickens from 42.2 to 10.2 micro mol/kg per min. in priming-injection + constant-infusion experiments tolbutamide again reduced Ra significantly. In all case Rd tended to fall, apparently as a result of the developing hypoglycaemia. tolbutamide did not affect the volume of extracellular fluid (sucrose space). In single-injection experiments , insulin (1 unit/kg injected i.v.) reduced Ra by 56% and transiently increased Rd by 39%. It was concluded that pancreatectomy and injection of insulin or tolbutamide produce responses in glucose movements in chickens that are qualitatively similar to those in mammals. In chickens the hypoglcaemic action of tolbutamide, which persists in the absence of the pancreas, depends on an inhibition of glucose release by the liver.

Animals↗
PubMed1982

Insulin responses to nonglucose stimuli in non-insulin-dependent diabetes mellitus during a tolbutamide infusion.

To determine the effect of tolbutamide on insulin release to nonglucose stimuli in non-insulin-dependent diabetes mellitus and how plasma glucose levels may modulate this effect, the acute insulin response (AIR) to an isoproterenol (12 Micrograms) or an arginine (5 g) i.v. pulse was determined before and during a tolbutamide infusion (7.5 mg/m2/min) in 25 male subjects. During the tolbutamide infusion, there was an increase in the AIR to both isoproterenol (% delta AIR = +49 +/- 21%, N = 11, P less than 0.05) and arginine (% delta AIR = +52 +/- 15%, N = 12, P less than 0.005) and a decrease in plasma glucose (delta plasma glucose for isoproterenol = -24 +/- 6 mg/dl, P less than 0.005; for arginine = -26 +/- 3 mg/dl, P less than 0.001). In separate studies, when the plasma glucose was clamped at baseline values by a variable rate of glucose infusion, there was a greater effect of tolbutamide on AIR when compared with the unclamped tolbutamide studies (isoproterenol: % delta AIR = +132 +/- 25%, P less than 0.025; arginine: % delta AIR = +95 +/- 12%, P less than 0.05). Thus, tolbutamide increases the AIR of nonglucose stimuli, but this augmentation by tolbutamide is blunted by the concomitant decrease in plasma glucose. Consideration of this observation is necessary when interpretating the effects of a sulfonylurea on islet cell responses.

Adult↗
PubMed1984

Effect of tolbutamide on myocardial metabolism and mechanical performance of the diabetic rat.

Exposure of the isolated, glucose-perfused rat heart to buffer containing 0.4 mM tolbutamide resulted in significant changes in both energy metabolism and myocardial contractility. In the nondiabetic, tolbutamide mediated only small increases in mechanical function at low atrial filling pressure, but this effect increased with increasing preload. By contrast, the stimulation of mechanical function resulting from exposure of the diabetic heart to tolbutamide was independent of preload. As a result, the tolbutamide-mediated, positive inotropic effect in the diabetic heart was greater at lower, but not higher, preload values than the effect in the nondiabetic. Moreover, the changes in energy metabolism initiated by tolbutamide were considerably larger in the diabetic. The most prominent effect was the mobilization of glycogen by tolbutamide in the diabetic, which was considerably greater than that observed in the nondiabetic. The drug also enhanced glucose utilization. The net effect of sulfonylurea exposure was to shift from preferential use of fatty acids as an energy source for contraction to use of glucose. Since the most prominent effect of the drug in the diabetic was the stimulation of glycogenolysis, it is concluded that tolbutamide can dramatically alter the metabolism of a tissue without acting through insulin.

Animals↗
PubMed1984

Tolbutamide stimulates fructose-2, 6-bisphosphate formation in perfused rat liver.

Effect of tolbutamide on liver fructose-2,6-bisphosphate (F-2,6-P2) was examined in isolated perfused rat liver in situ with a flow-through method. Tolbutamide (1 mM) gradually increased liver F-2,6-P2 level from 7.4 +/- 1.6 to 21.2 +/- 1.6 pmol/mg wet wt for 20 min perfusion. The increase of liver F-2,6-P2 induced by tolbutamide was dose dependent and was significantly observed at 10 min perfusion. The maximum plateau level of F-2,6-P2 induced by 16.7 mM glucose was further increased with 1 mM tolbutamide. Glucagon (10(-11) M) decreased the elevated level induced by 16.7 mM glucose, but this effect was completely inhibited with 2 mM tolbutamide. Cyclic AMP level of the liver throughout the perfusion with tolbutamide did not change. Carboxytolbutamide or gliclazide perfusion did not change significantly the liver F-2,6-P2 level; however, the results suggest that tolbutamide may increase the liver F-2,6-P2 level by affecting the phosphorylation state of fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase through cyclic AMP-dependent protein kinase, resulting in the stimulation of glycolysis and the inhibition of gluconeogenesis in the liver. Thus, the extrapancreatic action and the mechanism of action of different sulfonylureas may differ.

Animals↗
PubMed1989

Tolbutamide as mimic of glucose on beta-cell electrical activity. ATP-sensitive K+ channels as common pathway for both stimuli.

It is accepted for insulin-secreting cells in culture that the closure of ATP-sensitive K+ channels causes the glucose-dependent depolarization of pancreatic beta-cells seen at subthreshold levels (less than 100 mg/dl) of glucose. The question remains for the more thoroughly studied beta-cells in freshly dissected intact islets, however, whether closure of these channels is responsible for subthreshold glucose-dependent depolarization and suprathreshold glucose-dependent regulation of membrane electrical activity. To answer this, we took advantage of the ability of tolbutamide, an orally active antidiabetic agent, to specifically inhibit ATP-sensitive K+ channels in pancreatic beta-cells to determine whether these channels are active at sub- and suprathreshold levels of glucose and whether channel closure by tolbutamide reproduces the electrophysiological effects of glucose stimulation. We recorded membrane electrical activity from freshly dissected adult mouse pancreatic islets exposed to various levels of glucose and tolbutamide. As previously found by others, tolbutamide depolarizes islet cells in the absence of glucose, but we have found that, although the depolarization can trigger Ca2+ action potentials (spikes), a glucose-dependent permissive factor may be required for the normal bursting pattern of spiking. More significantly, we found that, unlike other beta-cell stimuli, tolbutamide specifically mimics the effects of glucose stimulation on the pattern of suprathreshold electrical activity. The effects were seen with levels of tolbutamide that correspond to those required to inhibit ATP-sensitive K+ channels. These data suggest that ATP-sensitive K+ channels are active at sub- and suprathreshold levels of glucose and may be the sole pathway by which either glucose or tolbutamide depolarizes beta-cells and controls beta-cell electrical activity.

Action Potentials↗
PubMed1997

Differences between the tolbutamide-boosted and the insulin-modified minimal model protocols.

The insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis (MINMOD) was compared with the tolbutamide protocol and the glucose clamp in 35 nondiabetic subjects (age 38 +/- 2 years [mean +/- SE], BMI 27.2 +/- 0.9 kg/m2). Each subject underwent two FSIGTTs, one with tolbutamide (300 mg) and the other with insulin (0.03 U/kg) and a euglycemic hyperinsulinemic clamp (40 mU x m(-2) x min(-1)). Insulin sensitivity was determined from each FSIGTT with MINMOD and from the clamp. Insulin sensitivity indexes (S(I)) from the two FSIGTTs were significantly correlated (r = 0.77, P < 0.001), but S(I(insulin)) was 29 +/- 4% lower than S(I(tolbutamide)). Both S(I(insulin)) and S(I(tolbutamide)) correlated significantly with S(I(clamp)) (r = 0.70 and 0.71, P < 0.001 for each). Expressed in the same units (dl/min per pU/ml), S(I(tolbutamide)) was on average 13 +/- 6% lower than S(I(clamp)) (4.51 +/- 0.40 vs. 5.36 +/- 0.36 x 10(-2), P = 0.009), whereas S(I(insulin)) was 44 +/- 4% lower. S(G(tolbutamide)) and S(G(insulin)) were not different (1.88 +/- 0.10 vs. 2.01 +/- 0.09 x 10(-2) min(-1), P = 0.167) and were significantly correlated (r = 0.50, P = 0.002). Thus, insulin sensitivity estimates from both protocols correlate significantly with each other and with the clamp. They are quantitatively discrepant, however, possibly due to differences in the route of insulin delivery, saturation of insulin action, and/or tolbutamide-induced proinsulin release. Data obtained from these two MINMOD protocols are not directly comparable, and the same protocol must be used in any single cross-sectional or longitudinal study.

Adult↗
PubMed2000

CYP2C19 participates in tolbutamide hydroxylation by human liver microsomes.

Tolbutamide is a sulfonylurea-type oral hypoglycemic agent whose action is terminated by hydroxylation of the tolylsulfonyl methyl moiety catalyzed by cytochrome P-450 (CYP) enzymes of the human CYP2C subfamily. Although most studies have implicated CYP2C9 as the exclusive catalyst of hepatic tolbutamide hydroxylation in humans, there is evidence that other CYP2C enzymes (e.g., CYP2C19) may also participate. To that end, we used an immunochemical approach to assess the role of individual CYP2Cs in microsomal tolbutamide metabolism. Polyclonal antibodies were raised to CYP2C9 purified from human liver, and were then back-adsorbed against recombinant CYP2C19 coupled to a solid-phase support. Western blotting revealed that the absorbed anti-human CYP2C9 preparation reacted with only recombinant CYP2C9 and the corresponding native protein in hepatic microsomes, and no longer recognized CYP2C19 and CYP2C8. Monospecific anti-CYP2C9 not only retained the ability to inhibit CYP2C9-catalyzed reactions, as evidenced by its marked (90%) inhibition of diclofenac 4'-hydroxylation by purified CYP2C9 and by human liver microsomes, but also exhibited metabolic specificity, as indicated by its negligible (<15%) inhibitory effect on S-mephenytoin 4'-hydroxylation by purified CYP2C19 or hepatic microsomes containing CYP2C19. Monospecific anti-CYP2C9 was also found to inhibit rates of tolbutamide hydroxylation by 93 +/- 4 and 78 +/- 6% in CYP2C19-deficient and CYP2C19-containing human liver microsomes, respectively. Taken together, our results indicate that both CYP2C9 and CYP2C19 are involved in tolbutamide hydroxylation by human liver microsomes, and that CYP2C19 underlies at least 14 to 22% of tolbutamide metabolism. Although expression of CYP2C19 in human liver is less than that of CYP2C9, it may play an important role in tolbutamide disposition in subjects expressing either high levels of CYP2C19 or a catalytically deficient CYP2C9 enzyme.

Animals↗
PubMed2002

Pharmacokinetics of tolbutamide after oral administration in rabbits with folate-induced renal failure.

The pharmacokinetic changes of tolbutamide were studied after oral administration to normal rabbits and mild and medium folate-induced renal failure rabbits. Tolbutmide 50 mg/kg was orally administered to the rabbits. The plasma concentrations of tolbutamide were significantly increased (p<0.05) at 9 to 24 hr in mild and medium folate-induced renal failure rabbits compared with those in normal rabbits. Therefore, the area under the plasma concentration-time curves (AUC) was significantly higher (p<0.05 and p<0.01 respectively) in mild and medium folate-induced renal failure rabbits (2906 microg/ml x hr and 4074 microg/ml x hr) than that in normal rabbits (2295 microg/ml x hr). The cumulative urinary excretion of tolbutamide was significantly decreased (p<0.05) in medium folate-induced renal failure rabbits (3.3 mg) compared with the normal rabbits (5.9 mg). The elimination rate constant (Kel) of tolbutamide was significantly slower in medium folate-induced renal failure rabbits (0.027 hr(-1)) than that in normal rabbits(0.044 hr(-1)). The terminal half-life of tolbutamide in medium folate-induced renal failure rabbits (25.5 hr) was significantly longer (p<0.01) than in normal rabbits (15.7 hr). These results could be considered as possibly due to inhibited excretion of tolbutamide metabolites or retarded metabolism of tolbutamide.

Acute Kidney Injury↗
PubMed1992

Effect of inflammation on the rabbit hepatic cytochrome P-450 isoenzymes: alterations in the kinetics and dynamics of tolbutamide.

In order to determine the effect of inflammation on the kinetics and dynamics of tolbutamide, two groups of seven and nine New Zealand rabbits received 50 mg/kg tolbutamide before and 48 hr after the production of an inflammatory reaction generated by the s.c. administration of turpentine in both hind legs. Tolbutamide in plasma and its two major metabolites (hydroxytolbutamide) and carboxytolbutamide in urine were assayed by high-performance liquid chromatography. The influence of inflammation on hepatic cytochrome P-450 was assessed by 1) determining the hepatic concentration in cytochrome P-450 and b5, 2) characterizing the activity of tolbutamide hydroxylase, 3) isolating hepatic microsomal protein bands by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 4) measuring the concentrations of hepatic cytochrome P-450 isozymes LM-2 and LM-3c. The inflammatory reaction induced a marked decrease in tolbutamide total body clearance, secondary to a reduction in its metabolic clearance. Concerning the metabolites, hydroxytolbutamide metabolic rate constant and the fraction of the dose recovered in urine as carboxytolbutamide were diminished. Tolbutamide hypoglycemic response was not significantly affected by the inflammatory process. The Vmax of tolbutamide hydroxylase was reduced from 14.6 +/- 2.3 to 5.6 +/- 1.4 nmol/mg/60 min (P less than .05), and the Km remained unchanged. The concentration of hepatic cytochrome P-450 was reduced in turpentine-treated rabbits, whereas the cytochrome b5 concentration remained the same in both groups. The systemic inflammation also reduced the content in the 48, 52, 54 and 60 kDa protein bands from hepatic microsomes and the concentration of the LM-3c form.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Separation of human liver microsomal tolbutamide hydroxylase and (S)-mephenytoin 4'-hydroxylase cytochrome P-450 enzymes.

Purification and immunoinhibition studies have suggested that the hydroxylations of (S)-mephenytoin and tolbutamide are catalyzed by rather similar forms of human liver cytochrome P-450 (P-450). However, the two activities are not well correlated in vivo; sulfaphenzaole is a selective inhibitor of tolbutamide hydroxylation, and expression of P-450 2C10 cDNA in yeast yields a protein that hydroxylates tolbutamide but not (S)-mephenytoin. The P-450 2C8, 2C9, and 2C10 cDNAs have all been isolated, and their sequences are known to be closely related (greater than 80%). Highly sensitive radiochromatographic assays were set up, and tolbutamide and (S)-mephenytoin hydroxylation activities were monitored during chromatography of human liver microsomal fractions. The two activities could be separated by chromatography, and proteins were purified to near-homogeneity that catalyzed either tolbutamide hydroxylation (P-450TB) or (S)-mephenytoin 4'-hydroxylation (P-450MP) but not both. Approximately 16 and 45% of the primary sequences of P-450TB and P-450MP, respectively, were determined by analysis of the tryptic peptides. The sequences of the P-450TB peptides matched those predicted by the P-450 2C9 and 2C10 cDNAs exactly; the P-450MP peptides showed two mismatches (of 219 residues) with the P-450 2C10 sequence. Proteins with the P-450 2C10 and P-450 2C9 sequences were expressed in Saccharomyces cerevisiae grown under different nutritional conditions, and both were found to be proficient in the hydroxylation of tolbutamide but not (S)-mephenytoin. We conclude, on the basis of this and previous work, that 1) P-450s 2C8, 2C9, and 2C10 all catalyze the hydroxylation of tolbutamide and 2) the protein involved in polymorphic (S)-mephenytoin 4'-hydroxylation is closely related to but distinct from P-450 2C8, 2C9, and 2C10.

Amino Acid Sequence↗
PubMed1990

Pharmacological interaction between tolbutamide and acetylsalicylic acid: study on insulin secretion in man.

This study has been planned to investigate some aspects of the interaction between acetylsalicylic acid (ASA) and tolbutamide on insulin secretion. In healthy subjects, oral administration of 3.2 g daily of ASA for 3 days significantly enhanced a) basal insulin levels (p less than 0.01), b) arginine-stimulated insulin secretion (25 g i.v. over 30 min) (p less than 0.01) and c) tolbutamide-stimulated insulin secretion (1 g or 0.25 g i.v. as a bolus) (areas under curves: p less than 0.02). Corresponding decreases in glycemia were observed. Tolbutamide binding to serum proteins was significantly reduced after ASA treatment (p less than 0.02). We conclude that, in case of tolbutamide test, interferences between ASA and tolbutamide on insulin secretion might be dependent, at least in part, on enhancement of free-tolbutamide percentage in plasma and not only on a direct or synergic action of ASA on pancreatic B-cell. Therefore, acute stimulation of insulin secretion by tolbutamide appears not to be completely comparable to other traditional stimuli, when ASA effects are studied.

Adolescent↗