Plasma Concentrations Of Tolbutamide Research Articles

Coleus forskohlii extract attenuates the hypoglycemic effect of tolbutamide in vivo via a hepatic cytochrome P450-mediated mechanism.

This in vivo study in rats evaluated whether Coleus forskohlii extract (CFE) taken orally interacted with tolbutamide, a hypoglycemic drug metabolized by CYP2C enzymes. Rats were fed 0%, 0.3%, 1% (w/w) CFE diet for 2 weeks, followed by 0% CFE diet for 1 day. They were then given 40 mg/kg tolbutamide by intragastric gavage. Blood glucose level was determined up to 6 h after tolbutamide administration. CFE treatment increased total CYP content and various CYP subtypes in the liver. In particular, increases in activity and protein expression were noted for the CYP2B, CYP2C, and CYP3A subtypes. CFE treatment dose-dependently attenuated both the hypoglycemic action of tolbutamide at 6 h and the plasma concentration of tolbutamide. The activity of (S)-warfarin 7-hydroxylase, a CYP2C enzyme was negatively correlated with plasma tolbutamide level, which also showed a negative correlation with the reduction of blood glucose level. These results indicate that CFE induced hepatic CYPs in rats and attenuated the hypoglycemic action of tolbutamide via a hepatic CYP2C-mediated mechanism.

Evaluation of the pharmacokinetic interaction between ticagrelor and tolbutamide, a cytochrome P450 2C9 substrate, in healthy volunteers

To assess the effect of ticagrelor on the pharmacokinetics of tolbutamide (a CYP2C9 substrate), and the effect of tolbutamide on ticagrelor pharmacokinetics. In this randomized, double-blind, two-period, crossover study, 23 healthy volunteers received either placebo or ticagrelor 180 mg twice daily (b.i.d.) for 9 days, with a single open-label oral dose of tolbutamide 500 mg on Day 5. After washout (14 days), volunteers received the alternate treatment. Plasma concentrations of tolbutamide, 4-hydroxytolbutamide, ticagrelor, and AR-C124910XX were determined for pharmacokinetic analyses. Ticagrelor had no effect on tolbutamide or 4-hydroxytolbutamide pharmacokinetic parameters. The geometric least square mean ratios for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from Time 0 to infinity (AUC0-∞) were lose to unity, and the 90% confidence intervals (CI) were within the range 0.80 - 1.25 for both tolbutamide and 4-hydroxytolbutamide. The terminal elimination half-life (t1/2), and time to maximal plasma concentrations (tmax) for tolbutamide and its metabolite were unaffected by ticagrelor coadministration. Tolbutamide had no effect on the Cmax, area under the concentration curve over the 2-hour dosing interval (AUC0-τ), t1/2 or tmax of either ticagrelor or AR-C124910XX. Coadministration of ticagrelor and tolbutamide was well tolerated. These results suggest that ticagrelor does not affect tolbutamide metabolism and is therefore unlikely to affect CYP2C9-mediated metabolism of drugs.

Effects of Bu-Zhong-Yi-Qi-Tang on hepatic drug-metabolizing enzymes and plasma tolbutamide concentration in rats

Ethnopharmacological relevanceBu-Zhong-Yi-Qi-Tang (BT) is the dry powder derived from the aqueous extract of a mixture of 10 medicinal herbs. It is a traditional Chinese medicine being used for the treatment of various immune-related diseases. Aim of the studyTo investigate the effect of BT on hepatic drug-metabolizing enzymes and its effect on plasma concentrations of tolbutamide, a substrate of CYP2C, in rats. Materials and methods: Exp 1Thirty-two male Wistar rats were divided into four groups. Rats were fed a control diet and a control diet containing 1, 2.5 and 5% (w/w) of BT, respectively, for eight weeks. The activities of the major CYP and Phase II conjugating enzymes in rat liver microsomes as well as the antioxidant system in rat liver were assessed. Exp 2: Male Wistar rats were fed a control diet or a control diet containing 2.5% of BT, respectively, for eight weeks. A single 20-mg/kg oral dose of tolbutamide was then administered to each rat. Plasma samples were collected from each rat at 0.5, 1, 2, 4 and 8h after dosing. The concentrations of tolbutamide and glucose level in plasma were determined by high-performance liquid chromatography-mass spectrometer (HPLC/MS) and enzymatic method, respectively. ResultsSignificant decrease in microsomal CYP2C-catalyzed diclofenac 4-hydroxylation in the liver of rats fed the BT diet was observed. Increased UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) activities were also observed in the liver of rats fed the diet containing 2.5 and 5% of BT. Immunoblot analyses also showed decreases of CYP2C11 proteins in the liver of BT fed rats. In addition, rats fed the 2.5% BT diet for eight weeks had no effects on the disposition of tolbutamide and reduction of glucose level in plasma after orally administered of tolbutamide. ConclusionsRats fed the BT diet for eight weeks may decrease CYP2C enzyme activity and protein expression and increase Phase II conjugating enzyme activities in liver. However, BT may not affect the disposition and efficacy of tolbutamide.

Effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide in protein-restricted rats

Effects of repeated administration of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide were examined in rats fed a low-protein diet. Rats were given a low (7% casein) or control (20% casein) protein diet for 21 days and administered Ginkgo biloba extract (100mg/kg per day) for the last 5 days. Tolbutamide was co-administered on the last day. Blood glucose and plasma tolbutamide concentrations were determined over the subsequent 12h and the activity of hepatic cytochrome P450s were determined at 12h after dosing. There were significant decreases in body weight, the ratio of liver to body weight, and plasma albumin concentrations in rats on the low-protein diet compared with controls. The hypoglycaemic effect of tolbutamide was significantly greater and the concentration of the drug in plasma was higher in the former group. The repeated administration of Ginkgo biloba extract had little influence on the hypoglycaemic effect of tolbutamide, but tended to decrease the drug concentration in plasma of control rats, while it reduced significantly the hypoglycaemic action and plasma concentration of tolbutamide in the protein-restricted rats. The effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide were significantly enhanced in rats on the low-protein diet.

Peritoneal Dialysis Alters Tolbutamide Pharmacokinetics in Rats with Experimental Acute Renal Failure

The plasma concentration profile of the antidiabetic agent tolbutamide was investigated in glycerol-induced acute renal failure (ARF) rats receiving or not receiving peritoneal dialysis (PD) to assess the impact of performing dialysis on tolbutamide pharmacokinetics. It was revealed that the plasma concentration of tolbutamide was decreased by 23.4% by performing PD in ARF rats, while it was not changed by PD in normal rats. The decrease in the plasma concentration of tolbutamide was nearly proportional to the increase in its volume of distribution. To clarify the mechanisms responsible for the decreased tolbutamide concentration caused by PD, the plasma protein binding of tolbutamide was examined in normal and ARF rats. The plasma unbound fraction of tolbutamide was higher in ARF rats than in normal rats, and the dissociation constants were 3.5+/-0.7 and 5.5+/-0.2 microg in normal and ARF rats, respectively. These results indicated that the unbound fraction of tolbutamide was increased in ARF rats because of its protein binding being suppressed. It is therefore likely that since a measurable amount of tolbutamide can distribute in peritoneal dialysate in ARF rats, but not in normal rats, the plasma concentration of tolbutamide was decreased by performing PD only in ARF rats. These findings suggest that diabetes medication with tolbutamide should be carefully performed in patients receiving dialysis treatment.

Effects of sho-saiko-to (xiao chai hu tang), a Chinese traditional medicine, on the gastric function and absorption of tolbutamide in rats.

This study was carried out to investigate the effects of Sho-saiko-to (Xiao Chai Hu Tang), a Chinese traditional medicine, on the gastric function including the gastric emptying rate (GER) and intragastric pH in rats. Additionally, the effects of the GER and intragastric pH on tolbutamide absorption after oral administration were examined. The GER measured at 40 min after dosing was reduced to about 70% by the pretreatment of Sho-saiko-to (500 mg/kg). The plasma tolbutamide concentration in the rats treated with a 250 mg/kg dose of Sho-saiko-to was significantly lower than that in the control group. Plasma tolbutamide concentrations increased along with the GER in the group co-administered Sho-saiko-to, and there were significant correlations between the GERs and plasma levels in both time points at 20 and 40 min after administration. In the study using pylorus-ligated rats, Sho-saiko-to significantly elevated the intragastric pH, but induced no change in the concentrations of tolbutamide dissolved in the gastric content. Additionally, Sho-saiko-to did not change the area under the plasma concentration-time curve (AUC) of tolbutamide up to 60 min after administration into the stomach loop, and gastric absorption has been considered to minimally contribute to whole absorption of tolbutamide in the gastrointestinal tract. These results indicate that Sho-saiko-to has an inhibitory effect on the function of gastric emptying in rats. The reduced gastric emptying could affect gastrointestinal absorption, resulting in the lower plasma concentration of tolbutamide after oral administration. Furthermore, it is suggested that Sho-saiko-to can raise the intragastric pH but affect neither the intragastric dissolution nor the gastric absorption of tolbutamide.

Interaction of a herbomineral preparation D-400, with oral hypoglycaemic drugs

D-400, a herbomineral preparation has proven antidiabetic activity in experimental models as well as in clinical trials. The possibility of concomitant use of this drug with sulphonylureas was explored in animal models. D-400 has been investigated for its interaction with oral hypoglycaemic agents namely, tolbutamide and glibenclamide in alloxan-induced diabetic rabbits. Administration of D-400 at a dose of 1 g/kg for 15 days significantly elevated plasma tolbutamide and glibenclamide concentrations with simultaneous reduction of blood glucose. Plasma tolbutamide and glibenclamide concentrations were significantly lowered after withdrawal of D-400 treatment. Elevation of plasma concentration of tolbutamide was observed only for the first 4 h after which it declined towards normal levels and no significant difference between D-400 treated and control group was observed at the end of 8 h. Significant elevation of plasma glibenclamide levels was observed at 2, 4 and 8 h with D-400 treatment. Incubation of D-400 with tolbutamide in plasma resulted in a significant increase in free tolbutamide levels.

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.

Kinetics of Drug-Drug Interactions in Sheep: Tolbutarnide and Sulfadimethoxine

The interaction between sulfadimethoxine and tolbutamide in sheep involving displacement from protein binding sites was investigated quantitatively. A 52% increase in the unbound plasma concentration of tolbutamide was observed in vitro at 37° after the addition of sulfadimethoxine (100μg/ml) to sheep plasma containing toibutamide (50μg/ml). Transient changes in tolbutamide's unbound and total plasma concentrations were noted after acute intravenous administration of sulfadimethoxine to sheep receiving a constant intravenous infusion of tolbutamide. These observations were consistent with displacement of tolbutamide from plasma and tissue binding sites and redistribution of the displaced tolbutamide into body water spaces. The steady state of both agents featured little change in the total plasma tolbutamide concentration, a 150% increase in the unbound plasma tolbutamide concentration, and an inhibition of tolbutamide oxidation by sulfadimethoxine. A model is presented and mathematical relationships are derived that permit a quantitation of the interaction and that indicate that sulfadimethoxine's constant of metabolic inhibition (KI) for tolbutamide metabolism is 65μg/ml.

The Use of a Solid Sampler in Chemical Ionization Mass Spectrometry for the Determination of Compounds Unstable Under Gas-Liquid Chromatographic Conditions-Analysis of Tolbutamide from Biological Fluid

Abstract A simple method for the quantification of tolbutamide in biological fluids is presented. It is suggested that the method can be applied to some compounds that are unstable under gas liquid chromatographic conditions. The procedure is based upon the introduction of biological extracts into the ionization source of the mass spectrometer by means of a solid probe. Upon evaporation from the probe the compounds are subjected to high pressure chemical ionization with methane as a reactant gas. The abundant M + 1 ions that are formed are measured quantitatively with reference to deuterium substituted internal standard. Plasma concentrations of tolbutamide in rabbit following intravenous administration of 100 mg of tolbutamide is described.