Clinical Pharmacokinetics of Sulphonylurea Hypoglycaemic Drugs

Balant, L

doi:10.2165/00003088-198106030-00003

Cited by 93 publications

(44 citation statements)

References 104 publications

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“…This concentration is well within the range of therapeutic plasma levels of free tolbutamide [24]. The tolbutamide sensitivity of the ATP-sensitive Kchannel in human B cells supports previous suggestions that the therapeutic action of sulphonylureas is mediated through inhibition of this channel.…”

Section: Discussionsupporting

confidence: 87%

“…Sulphonylureas increase plasma insulin levels in man [24], stimulate insulin release from isolated rodent islets [25] and inhibit the ATP-sensitive K-channels of rodent 593 B cells [5]. It has therefore been postulated that the ability of these drugs to stimulate insulin release in man results from inhibition of the ATP-sensitive K-channel.…”

Section: Effects Of External Tolbutamide On Whole-cell Currentsmentioning

confidence: 99%

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The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells

et al. 1989

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Summary. The ATP-and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 p~mol/l ATP (with 2 mM Mg 2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATPsensitive K-currents half-maximally at 18 ~tmol/l; the sensitivity to tolbutamide ~vas somewhat less in the inside-out patch.Ca-activated K-channels were unaffected by tolbutamide (10 mmol/1). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.Key words: ATP-sensitive K-channel, pancreatic B cell, human islet, sulphonylurea, tolbutamide, insulin secretion.The activity of the ATP-sensitive K-channel is thought to play a central role in the physiological regulation of insulin secretion from the pancreatic B-cell [1,2]. Studies of rodent B cells and B cell lines have led to the proposal that an increase in the cytosolic ATP/ADP ratio, resulting from glucose metabolism, inhibits channel activity. This produces membrane depolarization and precipitates a chain of events that culminates in insulin secretion.The channel is also the target for the hypoglycaemic sulphonylureas used clinically in the treatment of Type 2 (non-insulin-dependent) diabetes mellitus. These drugs inhibit channel activity in rodent B cells [3][4][5][6][7] and thereby stimulate electrical activity and insulin release [8]. It has therefore been suggested that a defect in the regulation of the ATP-sensitive K-channel may be involved in the initial pathology of Type 2 diabetes [9].Information about the properties of this channel in man is scarce. We have shown previously that the normal human B-cell possesses a K-channel inhibited by both ATP and the sulphonylurea, tolbutamide [9]. A similar channel is also found in human insulinoma ceils [10]. In this paper we present a detailed analysis of the properties of the ATP-sensitive K-channel of the human B cell. Our results indicate that the rodent B cell constitutes a good model for that of the human and provide support for the idea that the therapeutic action of tolbutamide in man is mediated via inhibition of the ATP-sensitive K-channel. Materials and methods PreparationHuman pancreata were removed (with permission) from nondiabetic, heart-beating cadaw.~r organ donors and islets of Langerhans isolated under aseptic conditions using a method similar to that described previously [11]. "[here were 2 male donors aged 27 and 37, and 3 female donors aged 19, 55 and 58. In brief, the pancreatic duct was cannulated and the pancreas distended with 2 ml/g prewarmed collagenase (6 mg/ml) in Iq[ank's solution. The pancreas was incubated in a water bath at 39~ for 25 rain then cooled rapidly in ice cold Hank's containing 20 mmol/1 HEPES and 5 g/1 bovine serum albumin....

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Section: Discussionsupporting

confidence: 87%

Section: Effects Of External Tolbutamide On Whole-cell Currentsmentioning

confidence: 99%

The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells

et al. 1989

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“…The complexation with cyclodextrins promoted an enhanced and faster TBM oral absorption, but only increased the hypoglycaemic effect, without any influence on its rate. The absence of proportional relation between TMB plasma concentration and pharmacodynamic effect was also observed by Balant (1981). For this reason, it is common that in TBM and other sulphonylurea studies, the pharmacodynamic effect is evaluated instead of the determination of drug plasma concentrations (Vila-Jato et al, 1987;Kedzierewicz et al, 1993;Torres-Labandeira et al, 1994;Babu and Pankit, 1995).…”

Section: Resultsmentioning

confidence: 96%

Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes

Veiga

Fernandes

Teixeira

2000

International Journal of Pharmaceutics

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The purpose of the present study was to evaluate the enhancement of tolbutamide (TBM) oral bioavailability and hypoglycaemic activity through complexation with b-cyclodextrin (b-CD) and hydroxypropyl-b-cyclodextrin (HP-b-CD). TBM and its freeze-dried inclusion complexes were administered to rabbits (New zealand breed; n =6), in a dose of 20 mg/kg. TMB plasma levels were measured by HPLC and glucose levels were analysed according to Trinder (Trinder, P., 1969. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann. Clin. Biochem. 6, 24-28). The pure drug attained a maximum of plasma concentration (C max ) of 18.5893.27 mg/ml at 8.5 h (T max ), whereas with inclusion complexes, C max increased about two times and appeared at ca. 4 h. AUC 0-24 of complexes was about 1.6 times as much as that of the pure drug. Thus, the extent of oral absorption of TBM from inclusion complexes was significantly greater and faster when compared with drug alone. In addition, without cyclodextrins the maximum hypoglycaemic effect (CVG max ) of TBM (34.1%) was observed at 5.6 h (Tg max ). CVG max of TBM/b-CD and TBM/HP-b-CD inclusion complexes were 34.1% (at 6.5 h) and 37.7% (at 5.1 h), respectively. AAC 0-24 of inclusion complexes was 1.4 times larger than that of pure drug. Hence, the oral administration of complexed TBM not only improved the drug absorption, but also the TBM hypoglycaemic activity.

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“…Our experimental data demonstrate that, within limits, such is the case. A similar situation was recently observed for the binding of tumour-promoting phorbol esters to lipo- The relative biological potency of each drug was judged from (A) the dose-action relationship for insulin release by pieces of rat pancreatic tissue [26,27]; (B) the dose-action relationship for the maximal fall in blood glucose concentration after oral administration to normal subjects [28]; (C) the dose-action relationship for the maximal decrease in blood glucose concentration after intravenous administration to normal conscious dogs [29]; (D) the doses causing a 30% decrease in blood glucose concentration after intravenous administration to normal healthy volunteers [30,31]; (E) the doses yielding comparable integrated glycaemic profiles after intravenous administration to normal subjects [32]; (F) the doses provoking comparable glycaemic decreases after oral or intravenous administration to normal subjects [33,34]; (G) the minimal therapeutic doses [11,35], chlorpropamide being excluded from this series because of its unusually long half-life; (H) the increments in glucose fractional removal rate (K value) observed after intravenous administration of a low dose (5 mg/kg body weight) of each drug to anaesthetized dogs [36,37]; and (K) the decrease in blood glucose concentration observed 2 h after oral administration of a low dose (10 mg/kg body weight) of sulphonylurea to monkeys [38]. In each column, the data are expressed relative to one another, according to the reference(s) cited.…”

Section: Discussionmentioning

confidence: 99%

Binding of hypoglycaemic sulphonylureas to an artificial phospholipid bilayer

Deleers¹,

Malaisse²

1984

Diabetologia

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Summary.Hypoglycaemic sulphonylureas bind to multilamellar liposomes formed of egg yolk phosphatidylcholine. In this artificial model, both specific and non-specific components of the binding phenomenon can be characterized by the same criteria as those used in studies performed with natural membranes. The relative ability of distinct sulphonylureas to inhibit the binding of 3H-glibenclamide or 3H-gliquidone to the liposomes parallels their relative potency as insulin secretagogues. It is proposed that the insertion of hypoglycaemic sulphonylureas into the phospholipid domain of the B cell membrane could represent a primary event in the mechanism by which these agents stimulate insulin release.

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Clinical Pharmacokinetics of Sulphonylurea Hypoglycaemic Drugs

Cited by 93 publications

References 104 publications

The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells

The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells

Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes

Binding of hypoglycaemic sulphonylureas to an artificial phospholipid bilayer

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