E. Wåhlin-Boll

Serum glibenclamide in diabetic patients, and influence of food on the kinetics and effects of glibenclamide

SummaryThe steady state concentrations of glibenclamide in serum were measured radioimmunologically in 37 diabetic patients after administration for at least a year. No other antidiabetic drugs had been given. The interindividual variation in glibenclamide concentrations was extremely large (0 to 1520 nmol/l), greatly exceeding the variation in dosage (2.5–25 mg daily). There was no relation between dose and serum concentration of glibenclamide. Only four (9%) patients had fasting blood glucose concentrations below 5.5 mmol/l, and fewer than half had values below 8 mmol/l. In most cases, therefore, the therapy was inadequate. Single-dose kinetics of glibenclamide was assessed in healthy volunteers. Food intake did not influence the bioavailability of a 5 mg dose of glibenclamide. There was no insulin increase in response to glibenclamide unless a meal was also given, and this increase was not significant until 1 h after administration of drug and meal, when the mean serum concentration of glibenclamide had reached 100nmol/l. Even in the fasting state, however, there was a progressive fall in blood glucose after glibenclamide administration, significant within 45 min and with a nadir at 2–2 1/2 h.

Influence of food intake on the absorption and effect of glipizide in diabetics and in healthy subjects

SummaryThe influence of a standardized breakfast on the single dose (5 mg) kinetics and effects of glipizide was examined in 9 healthy volunteers and in 14 diabetics not previously exposed to a sulfonylurea. In the volunteers, glipizide caused an increase in plasma insulin and a reduction in blood glucose both during continued fasting and when the drug was taken with the breakfast. Food intake did not influence the peak concentration, the elimination half-life or the bioavailability of the drug. However, food intake significantly delayed the absorption of glipizide by about 0.5 h. In the patients, glipizide produced a significant increase in plasma insulin and a significant diminution of the rise in blood glucose in response to the meal. Starting at breakfast and for 45 min thereafter serum glipizide concentrations were significantly higher when the drug was taken 0.5 h before the meal, than when ingested concurrently with it. With the former treatment, the increase in plasma insulin occurred earlier and the blood glucose reduction was pronouncedly greater than with the latter treatment. As the absorption of glipizide may be delayed by concurrent breakfast, this may help to explain, why the administration of glipizide 0.5 h before breakfast led to a more appropriate relation between the serum concentration of the drug and the metabolic impact of the meal, thereby promoting more appropriate insulin release and better glucose disposition than after concurrent intake of the drug and breakfast.

Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans

Objective To examine the relationship between plasma glyburide concentrations (0, 50, 100, 200, 400, and 800 nM) and the insulin response and glucose metabolism during euglycemic (4.6 ± 0.1 mM) and hyperglycemic (11.6 ± 0.2 mM) conditions. Research Design and Methods Nine healthy subjects participated in the study. Steady-state plasma glyburide concentrations were achieved by primed continuous intravenous infusion of glyburide. Results During both euglycemia and hyperglycemia, glyburide enhanced insulin secretion and glucose disposal only to drug levels of 100–200 nM corresponding to an oral dose ≤ 10 mg. Conclusions The data suggest that glyburide (and probably other sulfonylureas), operates within a narrow range of plasma concentrations (50–200 nM), which can be achieved with very low doses of the drug. It remains to be shown whether the threshold of maximal effect also in clinical practice is achieved with lower sulfonylurea doses than that currently used.

Accumulation of atenolol and metoprolol in human breast milk

SummaryPassage of the cardioselective beta adrenoceptor antagonists atenolol and metoprolol from serum to breast milk was assessed in 7 lactating women treated with atenolol due to hypertension developing during pregnancy, and in 3 healthy women who agreed to take metoprolol at cessation of lactation. For both drugs, the concentration in breast milk was higher than that in serum at every time studied, and the resulting AUC values were 1.5–6.8 times (atenolol) and 2.6–3.7 times (metoprolol) greater in milk than in serum. Assuming ingestion of 75 ml milk per meal, and as the maximum milk concentrations recorded were 6.35 µmol/l (atenolol) and 2.58 µmol/l (metoprolol), the data indicate that the dose following a meal at the time of maximum maternal drug concentration would not exceed 0.13 mg atenolol and 0.05 mg metoprolol, and would be considerably less after the other meals. In the only infant from whom serum samples could be obtained, the plasma atenolol concentration ranged between 0 and 0.26 µmol/l. None of the atenolol-exposed infants had any sign of an effect of the beta blocker. It would seem likely that, unless renal (atenolol) or hepatic (metoprolol) function in the infant were pronouncedly impaired, breast feeding need not be interrupted due to maternal medication with ordinary doses of either of these drugs. However, the infants should be observed for signs of beta blockade.

Impaired effect of sulfonylurea following increased dosage

SummaryTen Type 2 diabetics were examined during long-term treatment, at two dosage levels, with chlorpropamide once daily and glipizide t.i.d. Drug concentrations were measured by gas chromatography and high-pressure liquid chromatography, respectively, plasma insulin (IRI) by radio-immunoassay, and blood glucose enzymatically. Both drugs gave continuous sulfonylurea exposure, even at the lower dosage, and the mean plasma concentrations were almost doubled after the increase in dose. Neither the IRI nor the glucose response to meals showed any therapeutic improvement following the increase in chlorpropamide dosage. The lower dosage of glipizide produced better glucose utilization than chlorpropamide. On the other hand, the increased dose of glipizide led to impairment instead of further improvement. As this was associated with enhanced rather than reduced IRI levels, the impairment might have been due to increased peripheral insulin resistance. Thus, glipizide offers a therapeutic advantage over chlorpropamide, but its effectiveness may be restricted not only by limitations set by the disease, but also by counter-regulatory mechanisms that develop during continuous exposure to sulfonylureas at high levels.

Food-Induced Reduction in Bioavailability of Atenolol

SummaryThe influence of food intake on the bioavailability of the beta-adrenoceptor blocker atenolol was assessed by measurement of its single-dose kinetics in ten healthy volunteers, who took 100 mg both in the fasting state and together with a standardized breakfast. Food intake significantly shortened the time to reach peak concentration (2.7 h vs 1.5 h), but caused a significant reduction in AUC values, the mean decrease being 20%. The elimination half-life was unaffected. Atenolol, which is relatively hydrophilic, is incompletely absorbed in the fasting state, and escapes first-pass metabolism. The present findings indicate that food intake causes further impairment of its absorption, even though the absorption rate may initially be enhanced. This contrasts with previous observations on the more lipophilic beta-adrenoceptor blockers propranolol and metoprolol.

High-pressure liquid chromatographic determination of acetylsalicylic acid, salicylic acid, diflunisal, indomethacin, indoprofen and indobufen.

SummaryA high-pressure liquid chromatographic technique was developed which allowed concurrent measurement of acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma. ASA was extensively deacetylated to SA not only in vivo but also in vitro, even in frozen plasma. The in vitro conversion could be prevented by physostigmine. In vivo, ASA was eliminated within few hours, whereas SA was continuously present following daily administration of conventional doses of ASA. A slight modification of a similar method, originally developed for naproxen determination [9], was found appropriate for measurement of the SA derivative diflunisal, of two non-SA antiinflammatory agents, indomethacin and indoprofen, and of a related anti-platelet agent, indobufen.

Excretion of paracetamol in human breast milk

SummaryBreast milk and plasma levels of paracetamol were monitored in 3 lactating women after ingestion of a single 500 mg dose of paracetamol. The paracetamol concentrations were consistently lower in milk, with a mean milk/plasma AUC ratio of 0.76. This value was in close agreement with the milk/plasma partition ratio of 0.81 foundin vitro, and could be related to quantitative binding differences between the two fluids. The half-lives of paracetamol in plasma and breast milk were almost identical, with an overall mean of 2.7 h. As less than 0.1% of the maternal dose would be present in 100 ml milk, breast feeding need not be discontinued due to paracetamol treatment in conventional dosage.

Bioavailability of acetylsalicylic acid and salicylic acid from rapid-and slow-release formulations, and in combination with dipyridamol

SummaryAcetylsalicylic acid (ASA) is a strong, irreversible inhibitor of platelet aggregation, but loses this activity following first-pass deacetylation to salicylic acid (SA). In order to compare the bioavailability of unchanged ASA from rapid- and slow-release formulations, the single-dose concentration profiles of ASA and SA were studied in healthy volunteers following intake of two different rapid-release (conventional and effervescent tablets) and three different slow-release (microencapsulated ASA in tablets and in capsules, and enteric-coated tablets) formulations of ASA, and of one slow-release formulation of sodium salicylate. Since anti-platelet therapy with ASA is often combined with dipyridamol, the influence of this drug was also examined. The concentrations of ASA and SA were measured by high-pressure liquid chromatography. While the bioavailability of SA from the 5 ASA formulations was essentially equal and similar to that of the salicylate formulation, the bioavailability and peak concentrations of ASA appeared to be the much greater after rapid-release than after slow-release formulations. Indeed, ASA was only rarely detected in systemic blood following intake of slow-release ASA. Co-administered dipyridamol did not significantly influence the kinetics of ASA or SA. It appears that rapid-release formulations of ASA should be prefered in anti-platelet therapy, either alone or in combination with dipyridamol.

Determination of glibenclamide and its two major metabolites in human serum and urine by column liquid chromatography

A simple reversed-phase liquid chromatographic method for the measurement of low concentrations of glibenclamide (glyburide) and its two major metabolites, 4-trans- and 3-cis-hydroxyglibenclamide, in human serum and urine has been developed. The compounds were extracted with n-hexane-dichloromethane (1:1). The UV detection wavelength was 203 nm. The minimum detectable serum level of glibenclamide was 1 ng ml (2 nM), and the relative standard deviation was 8.9% (n = 9). When maximum sensitivity was desired the metabolites were chromatographed separately. Metabolites in urine were measured by the same method after five-fold sample dilution. The utility of the method was tested on a healthy volunteer who ingested 3.5 mg of glibenclamide. The parent drug was present in the serum for at least 18 h, and the metabolites in the urine for at least 24 h.