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PubMed1990

Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily.

Previous biochemical studies have suggested that tolbutamide and mephenytoin are metabolized by the same cytochrome P450 enzyme. Conversely, clinical studies indicate the involvement of different P450 forms in tolbutamide and mephenytoin metabolism. Our objective was to elucidate further those P450 enzymes responsible for hydroxylation of these two drugs. We studied both tolbutamide and (S)-mephenytoin hydroxylation in microsomes from 38 different normal adult human livers, and found large variability in the rates of metabolism for both reactions (1.75-47.4 nmol/mg/hr for hydroxytolbutamide formation and 0.1-7.2 nmol/mg/hr for 4-hydroxymephenytoin formation). No significant correlation was found between the two activities. However, both reactions shared common inhibitors in vitro, including inhibition by antikidney-liver-microsome autoantibodies (Meier and Meyer, Biochemistry 26: 8466-8474, 1987) and by teniposide. Two human liver cDNAs for P450s of the CYP2C subfamily designated IIC8 and IIC9 (S. Kimura, J. Pastewka, H. V. Gelboin and F. J. Gonzalez, Nucl. Acids Res. 15: 10053-10054, 1987), were functionally expressed in human HepG2 and TK- cells using a vaccinia virus vector. Interestingly, tolbutamide was hydroxylated by both expressed P450s. Only IIC9 catalyzed the 4-hydroxylation of (R)-mephenytoin and neither enzyme metabolized (S)-mephenytoin. We conclude that tolbutamide and (R)-mephenytoin are both metabolized by the same P450 enzyme, IIC9, and that tolbutamide is hydroxylated by an additional highly related enzyme, IIC8, contributing to the lack of correlation of the two hydroxylase activities among human liver microsomes and indicating the absence of a monogenically controlled polymorphism for tolbutamide.

Cell Line↗
PubMed1986

A new aspect of serum protein binding of tolbutamide.

Tolbutamide is known to bind highly to serum proteins. Quite different values have, however, been reported for binding, ranging from 80 to 99 percent. In this study, in vivo and in vitro binding of increasing concentrations of tolbutamide to human serum proteins were evaluated. In vitro studies were done serum from three healthy males and for in vivo studies serum samples from eight healthy males who had received 1,000 mg tolbutamide were used. Protein binding was determined by equilibrium dialysis, using DIANORM system. Tolbutamide concentrations were determined by HPLC method of Uihlein and Hack. The results suggest that there is an increase in percent tolbutamide bound with increasing concentrations of tolbutamide. Generally, an inverse relationship between the total concentration of a drug in serum and its bound fraction is observed. Our findings seem to be contrary to this, at least within the concentration range studied. There exist at least two binding sites on albumin with different affinities for tolbutamide and most probably, at low concentrations, the drug binds mainly to the high affinity sites, whereas at higher concentrations additional drug will bind to the lower affinity sites leading to the observed increase in fraction bound with concentration. In conclusion it may be said that serum protein binding is a much more complicated phenomenon than generally stated and that the normal observations are only true for some ideal compounds where only one site of adsorption has to be taken into account.

Blood Proteins↗
PubMed1982

No effect of propranolol and metoprolol on tolbutamide-stimulated insulin-secretion in hypertensive diabetic and non-diabetic patients.

In a double-blind cross-over study, we compared the effects of placebo, propranolol and metoprolol on tolbutamide-stimulated insulin-secretion in 10 non-insulin-dependent hypertensive diabetics and in 10 hypertensive non-diabetic patients. The patients were randomly allocated to two weeks each of treatment with placebo, propranolol 80 mg or metoprolol 100 mg b.i.d. At the end of each period, an intravenous tolbutamide tolerance test (IVTT, 200mg of tolbutamide i.v.) was performed, which caused a significant rise in peripheral insulin levels, leaving blood glucose concentrations unchanged. Tolbutamide-induced insulin-secretion was unaffected by pretreatment with beta-blockers when blood glucose concentrations were unchanged during the test. Since the serum-concentrations achieved with 200 mg of tolbutamide i.v. are similar to those reported during oral tolbutamide therapy, there seems to be no clinically significant interaction between beta-blockers and tolbutamide with respect to insulin-secretion.

Clinical Trials as Topic↗
PubMed1977

Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole.

Tolbutamide half-life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n = 2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2). The rate of elimination of tolbutamide was decreased within 1 to 2 hr of a single dose of sulfaphenazole and the tolbutamide half-life was increased from 9.2 hr to 25.7 hr (n = 2). In contrast, phenylbutazone and oxyphenbutazone, administered as single oral doses of 800 mg, had no immediate effect on tolbutamide elimination. At times greater than 20 to 30 hr after the single dose of phenylbutazone or oxyphenbutazone the rate of tolbutamide elimination was decreased. It is suggested that phenylbutazone and oxyphenbutazone act by inducing form of cytochrome P-450 with low activity for tolbutamide hydroxylation, whereas sulfaphenazole acts by direct inhibition of the microsomal mixed function oxidase system.

Adult↗
PubMed1987

Particle design of tolbutamide in the presence of soluble polymer or surfactant by the spherical crystallization technique: improvement of dissolution rate.

Poorly soluble crystals of tolbutamide were modified in the presence of a soluble polymer or surfactant by the spherical crystallization technique, the objective being to improve the dissolution rate and to transform platelet crystals into spherical agglomerates. An HCI solution was added to a tolbutamide:NaOH solution containing a water-soluble polymer or surfactant. The tolbutamide crystals were agglomerated with either and were free flowing and spherically compact. The size of the crystals of the agglomerate depended on the viscosity of the solvent and adsorption of the surfactant onto the crystal surface. The tolbutamide-agglomerated crystals dissolved isotropically, with no evidence of disintegration. The dissolution process was described in terms of the Hixson-Crowell equation. The dissolution rate of the agglomerate was 8 times faster than that of conventionally crystallized tolbutamide. Therefore, the solubility and flow-ability of tolbutamide can be improved using the spherical crystallization technique.

Crystallization↗
PubMed2001

An aqueous extract of the green leafy vegetable Ipomoea aquatica is as effective as the oral hypoglycaemic drug tolbutamide in reducing the blood sugar levels of Wistar rats.

This study was undertaken to compare the oral hypoglycaemic activity of an aqueous extract of the green leafy vegetable Ipomoea aquatica (dose equivalent to 3.3 g starting material /kg body weight) with that of the known oral hypoglycaemic drug tolbutamide (15 mg/kg body weight) in glucose challenged Wistar rats (3 g/kg body weight, administered 30 min after the administration of Ipomoea aquatica or tolbutamide). One and half hours after administration of glucose (equivalent to 2 h after administration of plant extract or tolbutamide), the mean blood glucose level of the Ipomoea aquatica treated group was 47.5% lower than that of the control group treated with distilled water. The tolbutamide treated group showed a mean blood glucose level which was only 33.8% lower than that of the control group. However, statistical analysis indicated that the blood glucose levels of the Ipomoea aquatica treated group were not significantly different from that of the tolbutamide treated group. Our results show that the aqueous extract of Ipomoea aquatica is as effectve as tolbutamide in reducing the blood glucose levels of glucose-challenged Wistar rats.

Administration, Oral↗
PubMed1987

Derivation of a quantitative measure of insulin sensitivity from the intravenous tolbutamide test using the minimal model of glucose dynamics.

Using the decay phase of the glucose response during an intravenous tolbutamide test, a minimal model of glucose dynamics was used to calculate a value for an "index of insulin sensitivity". This index describes the efficiency of insulin in accelerating the instantaneous rate of glucose disposal, and provides a measure of insulin resistance. The validity of estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test have been assessed with reference to estimates of this index derived from the intravenous glucose tolerance test for which the model was originally designed. There were three studies: (A) estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test in a group of normal, healthy men and women were compared with results obtained in a comparable group of subjects using the intravenous glucose tolerance test. The two methods gave estimates of the index of insulin sensitivity that were identical; (B) A group of patients taking methandienone, an anabolic steroid previously shown to cause marked insulin resistance, were tested whilst taking the steroid and either before, or at least two months after treatment. Each patient was tested by both intravenous tolbutamide test and intravenous glucose tolerance test on both occasions. Estimates of the index of insulin sensitivity from intravenous glucose tolerance or intravenous tolbutamide procedures both on and off treatment were significantly correlated (off treatment: rs = 0.71, n = 9, p less than 0.05; on treatment: rs = 0.69, n = 9, p less than 0.05); (C) A group of patient undergoing investigations for suspected disturbances in carbohydrate metabolism was studied, each patient having had both an intravenous tolbutamide and intravenous glucose tolerance test.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Regulation of energy metabolism in pancreatic islets by glucose and tolbutamide.

The kinetics of insulin secretion and oxygen uptake in response to D-glucose and tolbutamide were compared in mouse pancreatic islets. In addition, the role of decreased ATP as a driving force for secretagogue-induced oxygen consumption was examined. D-glucose (10-30 mmol/l) triggered a biphasic insulin release which always coincided with a monophasic increase in islet oxygen uptake. In the presence of D-glucose (5-30 mmol/l), tolbutamide (3-500 mumol/l) consistently elicited an initial peak of insulin secretion which was followed by a continued decline. Tolbutamide-induced secretory profiles were accompanied by similar respiratory profiles. Oxygen consumption per ng of insulin released during the test phase was higher after elevation of the glucose concentration than after addition of tolbutamide. In conjunction with 5 or 10 mmol/l D-glucose, but not with 15 or 30 mmol/l D-glucose, tolbutamide (30-100 mumol/l) lowered islet ATP content significantly (p less than 0.02). Phosphocreatine was not found in isolated islets, although they contained substantial creatine kinase activity. It is concluded that the driving force for tolbutamide-induced oxygen uptake is a decrease in the phosphorylation potential caused by the work load imposed by stimulation of the secretion process. However, a major proportion of the respiratory response to glucose also results from enhancement of biosynthesis.

Animals↗
PubMed2003

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

The pharmacokinetic of tolbutamide was studied after the oral administration to normal rabbits or rabbits with mild to medium folate-induced renal failure. The plasma concentrations of tolbutamide were significantly elevated (p<0.05) during 9 to 24 h in rabbits with mild or medium folate-induced renal failure. Consequently, the area under the plasma concentration-time curves (AUC) was significantly higher in mild (p<0.05) and medium (p<0.01) folate-induced renal failure rabbits (i.e., 2906 microg/mL x h for mild renal failure and 4074 microg/mL x h for moderate renal failure) than that in normal rabbits (i.e., 2295 microg/mL x h). The cumulative urinary excretion of tolbutamide was significantly depressed (p<0.05) in medium folate-induced renal failure rabbits (i.e., 3.3 mg) compared with that in normal rabbits (i.e., 5.9 mg). The elimination rate constant (Kel) of tolbutamide was significantly decreased in medium renal failure rabbits (i.e., 0.027 h(-1)) than that in normal rabbits (i.e., 0.044 h(-1)); As a result, the terminal half-life of tolbutamide in medium folate-induced renal failure rabbits (i.e., 25.5 h) was significantly longer (p<0.01) than that in normal rabbits (i.e., 15.7 h). The change in pharmacokinetic parameters is consistent with the hypothesis that the alteration is mediated by the depressed metabolic elimination of the drug by the induction of renal failure. Therefore, these observations indicated that the dosage adjustment may be necessary for tolbutamide in patients with renal insufficiency.

Administration, Oral↗
PubMed2006

Biotransformation of tolbutamide to 4'-hydroxytolbutamide by the fungus Cunninghamella blakesleeana.

The hypoglycemic drug tolbutamide is commonly used as a probe drug to evaluate CYP2C9 enzyme activity in terms of production of 4'-hydroxytolbutamide. In the present study, an initial screening of seven filamentous fungi was carried out to identify which was most competent to transform tolbutamide into 4'-hydroxytolbutamide. From this screening, the fungus Cunninghamella blakesleeana AS 3.910 was selected as a suitable bioconverter. At a concentration of 1.2 mg ml(-1), the growing fungus transformed 95.0% of tolbutamide into 4'-hydroxytolbutamide in 96 h. With resting culture, the yield could reach 91.7% and exceeded 91.0% even when the tolbutamide concentration was increased to 4.0 mg ml(-1). On scale-up to 3 l buffer containing 12.0 g tolbutamide, 90% of tolbutamide was transformed into 4'-hydroxytolbutamide in 96 h. Work-up of the broth by column chromatography and recrystallization yielded 6.5 g (53.9% recovered) of 4'-hydroxytolbutamide with a purity of more than 99%. These results suggest C. blakesleeana AS 3.910 is a useful biosynthetic tool in the preparation of 4'-hydroxytolbutamide.

Biotransformation↗
PubMed1999

Direct effects of tolbutamide on mitochondrial function, intracellular Ca2+ and exocytosis in pancreatic beta-cells.

Using the whole-cell voltage-clamp method to measure ATP-sensitive K+(KATP) currents, changes in cell capacitance to measure secretion and microfluorimetry to monitor intracellular Ca2+ and mitochondrial function, we have investigated the direct effect of sulphonylureas on exocytosis in pancreatic beta-cells. Tolbutamide (100 microM) and 100 nM 4-beta-12-phorbolmyristate-13-acetate (PMA), which activates the protein kinase C (PKC) isoforms found in beta-cells, potentiated exocytosis in a non-additive manner. These effects were blocked by down-regulation of PKC. Our data support the idea that tolbutamide can potentiate secretion from beta-cells via a PKC-dependent pathway. Because PKC and sulphonylureas can modulate the activity of KATP channels, we explored whether the above effects are caused by inhibition of this channel. PMA increased whole-cell KATP currents but did not affect their sensitivity to tolbutamide. Down-regulation of PKC affected neither the magnitude nor the tolbutamide sensitivity of the KATP current. Both tolbutamide and the mitochondrial uncoupler FCCP (1 microM) mobilized intracellular Ca2+ and prolonged Ca2+ transients elicited by cholinergic mobilization of intracellular Ca2+ stores. Tolbutamide (0.1-0.5 mM), like FCCP, depolarized the mitochondrial membrane potential and activated KATP currents. We suggest that sulphonylureas can directly potentiate exocytosis by impairing mitochondrial function and Ca2+ handling, which ultimately leads to activation of Ca2+-dependent enzymes such as PKC.

Adenosine Triphosphate↗
PubMed1991

Inhibition of gluconeogenesis by tolbutamide in isolated rat hepatocytes: modulation of glucose-6-phosphate substrate cycle.

In hepatocytes isolated from 24-hour fasted rats, the oral hypoglycemic agent tolbutamide (1 mmol/L) inhibited glucose formation from different concentrations (1 to 20 mmol/L) of galactose, dihydroxyacetone, glycerol, and a mixture of L-lactate:pyruvate (molar ratio, 10:1). Parallel to the reduction of gluconeogenesis, tolbutamide stimulated L-lactate formation when cells were incubated with either galactose, dihydroxyacetone, or glycerol. All these tolbutamide effects occurred without significant modification of hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) levels. Only when glucose was included in the incubation medium was the inhibition of gluconeogenesis caused by the sulfonylurea accompanied by a significant increment of the cellular F-2,6-P2 concentration. Under these conditions, tolbutamide potentiated the effect of glucose in promoting the increase of this regulatory metabolite, as well as the stimulation of glycolysis; in addition, tolbutamide increased the cellular pool of hexose-6-phosphates and the rate of tritium release from (2-3H)glucose. These results support the hypothesis that tolbutamide regulates hepatic glucose metabolism, at least, by modulating the glucose-6-phosphate substrate cycle.

Animals↗
PubMed1988

Tolbutamide affects food ingestion in a manner consistent with its glycemic effects in the rat.

The sulphonylurea tolbutamide possesses the ability to stimulate insulin release, produce hypoglycemia and increase food intake; however, no study has investigated the effects of moderate doses which do not produce frank hypoglycemia. Forty male rats received injections of tolbutamide at 0, 5, 15, 25 or 50 mg/kg body weight. The injections terminated a 2-hr fast and occurred at light offset, insuring a meal. Food intakes were then recorded for two hr following injection. Tolbutamide at 5 and 15 mg doses decreased food intake during the first half-hour or hour, respectively. In parallel experiments, 10 rats were sampled for blood prior to injection of tolbutamide or saline at doses cited above, and again at 10 and 40 min following injection in the absence of food. Plasma was then analyzed for insulin and glucose. Both 5 and 15 mg tolbutamide produced a mild, reliable increase in insulin accompanied by a decrease of 5 to 15 mg/dl in plasma glucose. On the other hand, the 50 mg dose produced a marked increase in insulin and a decrease of approximately 25% in plasma glucose. Thus, the present studies suggest that when endogenous insulin levels are modestly raised by tolbutamide, such that only moderate reductions of circulating glucose were observed, decreases in food intake occur.

Animals↗
PubMed1991

Possible mechanism of proteolysis for the extrapancreatic action of tolbutamide.

In order to assess the mode of the extrapancreatic action of the sulfonylureas, we evaluated the contribution of a proteolytic mechanism for sulfonylurea action by analyzing the effects of a protease inhibitor on insulin- or tolbutamide-stimulated liver fructose-2,6-bisphosphate (F-2,6-P2) formation using isolated rat hepatocytes. The F-2,6-P2 level in hepatocytes was significantly increased by the addition of insulin or tolbutamide. The stimulatory effect of insulin on the F-2,6-P2 formation was most significant when its level was reduced by the addition of 2 microM of forskolin. Insulin action on F-2,6-P2 formation was inhibited by the addition of a protease inhibitor, p-tosyl-L-arginine methyl ester hydrochloride (TAME). Tolbutamide (2 mM) significantly increased hepatocyte F-2,6-P2 level (P less than 0.01 vs the control level). In the presence of TAME, the stimulatory effect of tolbutamide was also suppressed. The present data suggest that a proteolytic mechanism is important in both insulin and tolbutamide action on the F-2,6-P2 formation, and it may be hypothesized that, like insulin, the chemical mediator of tolbutamide action is formed proteolytically.

Animals↗
PubMed2004

Is acarbose equivalent to tolbutamide as first treatment for newly diagnosed type 2 diabetes in general practice? A randomised controlled trial.

We performed a double blind randomised controlled trial in general practice to assess equivalence between tolbutamide and acarbose with respect to the effect on mean HbA(1c) in newly diagnosed patients with type 2 diabetes. Secondary objectives were to compare the effects of both treatments on fasting and post-load blood glucose and insulin levels, lipids, and adverse events. Patients were randomised to receive acarbose, titrated step-wise to a maximum of 100mg three times daily (n=48) or tolbutamide, similarly titrated to a maximum of 2000 mg in three doses (n=48). The two treatments were considered equivalent if the two-sided 90% confidence interval (CI) for the difference in mean HbA(1c) levels was within the range -0.4 to 0.4%. Results were analysed on an intention-to-treat, per-protocol and on worst-case basis. Both agents reduced the HbA(1c) percentage and fasting blood glucose levels. The difference in mean decrease of HbA(1c) was 0.6% in favour of tolbutamide (90% CI 0.3, 0.9; 95% CI 0.2, 1.0). A worst-case analysis, assuming no change in HbA(1c) for dropouts, yielded a difference in mean decrease of 0.9% (90% CI 0.6, 1.2) in favour of tolbutamide. The difference in mean decrease of fasting blood glucose was 1.0 mmol/l in favour of tolbutamide (95% CI 0.3, 1.7). There were no significant differences in post-load blood glucose, fasting and post-load insulin levels, or lipids. In the acarbose group significantly more patients (15 versus 3) discontinued therapy because of adverse effects, mostly of gastrointestinal origin. We conclude that the results of this study favour tolbutamide over acarbose as first treatment for patients with newly diagnosed type 2 diabetes.

Acarbose↗
PubMedDate not supplied

Glucose and the insulin-releasing drug tolbutamide attenuate the effects of morphine and angiotensin on alcohol consumption.

Animals studies have shown that insulin injections reduce alcohol intake, implicating glucoregulatory processes in alcohol consumption. Angiotensin (ANG) II reduces alcohol intake and promotes glycogen breakdown in the liver but no studies have assessed the role of glucoregulatory processes in ANG II's effect. Similarly, glucose injections attenuate the analgesic and cognitive effects of opiates, yet no studies have assessed the effect of glucose on the well-documented ability of opiates to enhance alcohol consumption. The present experiments further examine the role of glucoregulatory processes in alcohol intake by assessing the effect of glucose injections on morphine-enhanced alcohol consumption and by evaluating the effect of the insulin-releasing drug, tolbutamide, on ANG II-reduced alcohol consumption. Adult male Wistar rats acquired alcohol drinking using the limited access procedure that offers daily 40-min access to both 6% w/v alcohol and water and ensures reliable alcohol drinking in bouts large enough to produce pharmacologically relevant intakes. Experiment 1: after intake stabilized, four groups of rats were first pretreated with vehicle injections and in the next phase, three of the four groups received either 50, 100, or 200 mg/kg glucose intraperitoneally (i.p.) prior to access to alcohol. Neither the vehicle injections nor any of the glucose doses had an effect on alcohol intake. In the final phase all groups continued to receive their respective glucose doses or vehicle but were now also treated with 5 mg/kg morphine sulphate i.p. prior to alcohol access. Morphine stimulated alcohol intake to a similar degree in all groups except the 200 mg/kg group, which showed a significant attenuation in morphine-enhanced alcohol intake. Experiment 2: after intake stabilized, different groups of rats were pretreated with vehicle injections and in the next phase received either 5, 25, 50, or 100 mg/kg tolbutamide or vehicle subcutaneously (s.c.) prior to alcohol access. The vehicle injections did not alter alcohol intake, and only the 100 mg/kg dose of tolbutamide produced a reduction in alcohol intake. In the final phase the groups continued to receive their respective doses of tolbutamide or vehicle but were also treated with 400 micrograms/kg ANG II s.c. immediately prior to alcohol access. ANG II reduced alcohol intake a similar extent in the groups pretreated with 5-50 mg/kg tolbutamide. However, the 100 mg/kg dose of tolbutamide significantly attenuated ANG II's ability to reduce alcohol intake. These results demonstrate that manipulations that engage glucoregulatory processes can influence the mechanism(s) by which morphine and angiotensin respectively increase and decrease alcohol drinking.

Alcohol Drinking↗
PubMed1998

Regulation by tolbutamide and diazoxide of the electrical activity in mouse pancreatic beta-cells recorded in vivo.

1. The glucose-dependence of beta-cell electrical activity and the effects of tolbutamide and diazoxide were studied in anaesthetized mice. 2. In untreated animals there was a direct relationship between glycaemia and the burst pattern of electrical activity. Animals with high glucose concentration showed continuous electrical activity. The application of insulin led to a steady decrease in blood glucose concentration and a transition from continuous to oscillatory activity at 7.7+/-0.1 mM glucose (mean+/-s.d.) and a subsequent transition from oscillatory to silent at 4.7+/-0.6 mM glucose. 3. At physiological blood glucose concentrations the electrical activity was oscillatory. The injection of tolbutamide (1800 mg kg[-1]) transformed this oscillatory pattern into one of continuous electrical activity. The increased electrical activity was associated with a decrease in blood glucose concentration from 7.1+/-0.9 (control) to 5.5+/-1.0 mM (10 min after tolbutamide injection). The effects of tolbutamide are consistent with a direct blocking effect on the K(ATP) channel that leads to membrane depolarization. 4. The injection of diazoxide (6000 mg kg[-1]) hyperpolarized the cells and transformed the oscillatory pattern into a silent one. This is consistent with a direct stimulant effect by diazoxide on the K(ATP) channel. The use of tolbutamide or diazoxide correspondingly led to the lengthening or shortening of the active phase of electrical activity, respectively. This indicates that in vivo, such activity can be modulated by the relative degree of activation or inhibition of the K(ATP) channel. 5. These results indicate that under physiological conditions, tolbutamide and diazoxide have direct and opposite effects on the electrical activity of pancreatic beta-cells, most likely through their action on K(ATP) channels. This is consistent with previous work carried out on in vitro models and explains the drugs hypo- and hyperglycaemic effects.

Animals↗
PubMed1999

Pharmacokinetics of tolbutamide in ethnic Chinese.

AIMS: Ethnic differences in drug disposition have been described for many drugs. Despite the widespread use of tolbutamide in Asian populations, the pharmacokinetics of tolbutamide, a CYP2C9 substrate, have not been described in ethnic Chinese. METHODS: The pharmacokinetics of tolbutamide (500 mg orally) were studied in 10 young, healthy volunteers (seven male/three female; age 21-29 years), each of whom had four ethnic Chinese grandparents. Plasma concentrations of tolbutamide were measured for 32 h post-dose by high performance liquid chromatography. The concentrations of hydroxytolbutamide and carboxytolbutamide were also measured in urine for 32 h post-dose. Noncompartmental pharmacokinetic parameters were calculated using standard equations and compared with those previously reported in Caucasian subjects using the Mann-Whitney U test. RESULTS: Pharmacokinetic parameters in Chinese (mean+/-s.d.) including Cmax (63+/-11 microg ml(-1)), tmax (median 3.3 h; range 1.6-6.0 h), V/F (9.1+/-1.7 l) and t1/2, (9.1 h; harmonic mean) were similar to the values in Caucasians. CL/F (637+/-88 ml h(-1)) was higher in Chinese than Caucasians. The urinary recoveries of hydroxytolbutamide (13+/-1% of dose) and carboxytolbutamide (68+/-5% of dose) and the partial apparent metabolic clearance (0.15+/-0.02 ml min(-1) kg(-1)) in Chinese were comparable with Caucasians. CONCLUSIONS: The pharmacokinetics of tolbutamide have been described in ethnic Chinese and the disposition is similar to that reported in Caucasians. This study suggests that there is no substantial ethnic difference in the tolbutamide hydroxylase activity of CYP2C9.

Adult↗