Insulin release by tolbutamide and glibenclamide

Summary Glibenclamide, a second generation sulfonylurea, produced the same pattern of insulin release from the perfused rat pancreas as did tolbutamide. The stimulatory effect was closely dependent on the glucose concentration present. Both agents enhanced insulin secretion at 5–10 mM glucose, whereas no additional insulin was released when maximally stimulating levels of glucose (20 and 30 mM) were present. The concentrations of glibenclamide stimulating insulin release were 100–400 times lower than equieffective levels of tolbutamide. At glucose levels of 3 or 8 mM, however, glibenclamide did not liberate significantly more insulin from the pancreas than did tolbutamide. Thus the differences of tolbutamide and glibenclamide were quantitative rather than qualitative. Although the active concentrations differed the effects produced were comparable.     

Dose-response relationships of tolbutamide and glibenclamide in diabetes mellitus

Summary Using a new procedure to study the dose-response relationships of sulphonylureas, the effects of tolbutamide and glibenclamide on blood sugar and serum insulin have been examined in 9 diabetic patients. Particular changes sought in serum insulin were alteration in the two initial peaks, elevation of basal levels and augmentation of the response to glucose infusions. In general, both sulphonylureas had identical effects and glibenclamide was not superior to tolbutamide. In 3 or 4 obese patients the first of the two initial insulin peaks was as high as in healthy volunteers, whereas the second peak was diminished; both initial peaks were greatly reduced in non-obses patients. The basal level of insulin was elevated in only one patient after glibenclamide. The response of insulin levels to glucose infusions was not increased in any patient and was actually inhibited by glibenclamide in one case. Tolbutamide produced its maximal effects after a dose of 1.0 g, glibenclamide after 1 mg. Blood sugar levels declined more rapidly in patients with latent diabetes than in those with the overt disease. In two of the latter, the fall in blood sugar was not associated with a corresponding increase in serum insulin.Dedicated to Prof. Dr. h. c. Hedwig Langecker on her 80th birthday.     

Comparative bioavailability of fluorouracil and its prodrug, ftorafur, following intra-arterial, intravenous and preoral administration]

The blood-plasma levels in 28 patients, suffering from colorectal cancer with liver metastases, which were treated by a cyclic chemotherapy with fluorouracil (1) after p.o. and intraarterial (i.a.) administration of 1 or its prodrug ftorafur (2), respectively, were compared with those obtained after i.v. administration and the pharmacokinetics were calculated. In the case of 1 as well as of 2 the i.a. administration has been found to be optimal for distribution into the tumor tissue of liver metastases due to lowered blood-plasma concentrations. The absolute bioavailability, was 78% for p.o. and 57% for the i.a. administration of 1 respectively, and 98% for p.o. and 61% for the i.a. administration of 1 (given as 2), Accordingly, p.o. administration of both substances leads to therapeutical sufficiently high plasma levels with a steady state of css = 2.9 micrograms/ml/tss = 14 min for 1 and css = 3.5 micrograms/ml/tss = 20 min for 2.     

Displacement of tolbutamide,glibenclamide and chlorpropamide from serum albumin by anionic drugs

The binding of tolbutamide, chlorproramide and glibenclamide to human and bovine serum albumin has been estimated in the presence of a number of acidic drugs. It is shown that agreement between experimental data and that calculated using the competitive binding equation is very poor. The degree of displacement of tolbutamide and chlorpropamide is much greater than that calculated using the equation while displacement of glibenclamide is much less. These findings suggest that displacement is essentially non-competitive and that glibenclamide is less susceptible to displacement by acidic drugs than tolbutamide or chlorpropamide.     

Desensitization of sulphonylurea- and nutrient-induced insulin secretion following prolonged treatment with glibenclamide

Functional effects of prolonged exposure to the sulphonylurea glibenclamide were examined in a popular clonal pancreatic beta-cell line, denoted as BRIN-BD11. In acute 20-min incubations, 200 microM of tolbutamide or glibenclamide stimulated insulin release from non-depolarized and depolarized cells, which was dramatically reduced following 18-h culture with 100 microM glibenclamide. Sulphonylurea desensitization in non-depolarized cells was reversed following 6-36-h subsequent culture in the absence of glibenclamide. However, desensitization of insulinotropic effects of sulphonylureas in depolarized cells following glibenclamide culture and associated decline in cellular insulin content was not fully reversible. Culture with 100 microM glibenclamide also markedly reduced the acute insulinotropic actions of glucose, L-alanine, L-arginine, 2-ketoisocaproic acid (KIC) and KCl. These effects were almost completely reversed following 18-h culture in the absence of the sulphonylurea.     

Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration

Eight healthy volunteers received 50 mg of dimenhydrinate, a theoclate salt of diphenhydramine, orally, sublingually, and intravenously on three separate occasions in random sequence. Plasma diphenhydramine concentrations during 12 h after each dose were measured by gas-liquid chromatography with nitrogen-phosphorous detection. Mean peak plasma concentrations after sublingual administration were slightly lower than after oral dosage (38.3 vs 47.8 ng ml-1), and the time of peak concentration was similar (2.6 vs 2.3 h after dose). These differences did not reach statistical significance. The mean total area under the plasma concentration-time curve (AUC) for sublingual administration was slightly but not significantly smaller than after oral dosage (221 vs 270 h ng ml-1). Systemic availability of diphenhydramine after sublingual dimenhydrinate, measured by the ratio of oral AUC to intravenous AUC, was slightly less than after oral dimenhydrinate (0.58 vs 0.69, NS), and both were significantly less than 1.0. Thus sublingual and oral administration of dimenhydrinate result in comparable, but incomplete, systemic availability of diphenhydramine.     

Midazolam pharmacokinetics following intravenous and buccal administration

Aims Midazolam has good anxiolytic qualities and is a well established premedication agent before anaesthesia or short surgical procedures. The objective of the present study was to determine pharmacokinetic data from individual plasma concentration profiles obtained following intravenous and buccal administration of midazolam.
Methods Eight young healthy volunteers received single doses of 5  mg midazolam i.v. and after a period of 1 week buccally in a cross over manner. Blood samples were obtained up to 480  min. The measurement of plasma midazolam concentrations was by gas-chromatography.
Results The maximum plasma concentration was 55.9  ng  ml⁻¹ (range 35.6–77.9  ng  ml⁻¹ ) at 30  min (range 15–90  min) following buccal administration. AUC was calculated to be 15 016  ng  ml⁻¹ min (s.d. 3778  ng  ml⁻¹ min) following i.v. and 11191  ng  ml⁻¹ min (s.d. 1777  ng  ml⁻¹ min) following buccal midazolam. This gave a mean midazolam bioavailabilty of 74.5%.
Conclusions The pharmacokinetic data presented in this study demonstrate a high bioavailability and reliable plasma concentrations following buccal midazolam. The clinical benefit of buccal midazolam may be in particular patient controlled premedication or sedation in adults.     

Meperidine pharmacokinetics following intravenous, peroral and buccal administration in beagle dogs

The pharmacokinetics of meperidine was studied in Beagle dogs following intravenous, peroral and buccal administration of a meperidine hydrochloride solution. The elimination half-life after I.V., P.O. and buccal routes was 0.75 +/- 0.14 hours, 0.93 +/- 0.18 hours and 0.36 +/- 0.10 hours, respectively. The volume of distribution and total clearance following I.V., P.O. and buccal administration were 2.41 +/- 0.34 L/kg and 42.5 +/- 8.9 ml/min/kg, 2.84 +/- 1.24 L/kg and 34.6 +/- 7.8 ml/min/kg, 1.01 +/- 0.52 L/kg and 34.7 +/- 8.0 ml/min/kg, respectively. The absolute bioavailability after P.O. and buccal administration was 11.0 +/- 6.8% and 11.9 +/- 6.6%, respectively. This paper discusses the observed low bioavailabilities on hypothesis of hepatic and lung first-pass effect. A hypothesis is presented to explain the delayed onset of absorption following buccal administration.     

Kinetics of lead following intravenous administration in man

Whole body retention of lead (Pb) and lead kinetics in blood, urine and faeces were determined over 2 weeks following i.v. administration of ²⁰³Pb-labelled chloride to 2 subjects. Pb was retained with a biological half-life of 73 days (mean). After day 1 Pb excreted in urine and faeces remained fairly constant at 1% and 0.3% of administered dose, respectively. There was a daily loss of 0.5% by other routes. There was a rapid clearance of isotope from plasma with a half-life of 1 min (mean). At 60 min 45% of the administered dose was in erythrocytes; this changed little over the 2 weeks.     

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.     

Pharmacokinetics of esomeprazole following varying intravenous administration rates

There are situations where the use of an oral proton pump inhibitors is not possible. In such situations an intravenous route is the preferred alternative. An intravenous formulation of esomeprazole has recently been developed. This study was designed to evaluate the pharmacokinetics and tolerability of single-dose intravenous esomeprazole using different rates of administration. The study was an open randomised, cross-over design in healthy male and female (n = 24). Esomeprazole 40 mg intravenously was administrated as an infusion over 10, 15, 20 or 30 min., or esomeprazole 20 mg intravenously as an injection over 3 min. There was a wash-out period of at least 6 days between dose regimens. It was demonstrated that increasing the rate of intravenous infusion of esomeprazole 40 mg resulted in higher Cmax values (geometric means; 5.2-7.6 micromol/l), but the AUC values remained relatively constant (7.1-7.2 micromor/l). As expected esomeprazole 20 mg administered as a 3 min. intravenous injection had lower Cmax (3.6 micromol/l) and AUC (2.9 micromol.r/l) values than any of the infusions of esomeprazole 40 mg. Intravenous esomeprazole was well tolerated in this study. In conclusion, any variation in the infusion rate of esomeprazole 40 mg intravenously has little effect on the pharmacokinetics of esomeprazole in healthy volunteers, which provides flexibility in the choice of dosing regimens.     

Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration

The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp.Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.