Preclinical Pharmacology of Biguanides

Wiernsperger, Nicolas

doi:10.1007/978-3-662-09127-2_12

Cited by 31 publications

(25 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). The fitting produced similar values of the rate constants of absorption and elimination from the GI lumen (k g0 and k gg , respectively; see Table 2), indicating an overall GI bioavailability of approximately 50%, which is in accordance with the 40 -60% bioavailability reported in most studies (Wiernsperger, 1996). The rate constant representing metformin elimination from the systemic circulation (k s0 ) was higher than the absorption rate constant, confirming flip-flop PK behavior of metformin (Scheen, 1996;Cusi and DeFronzo, 1998).…”

Section: Pk-pd Analysis Of Metforminsupporting

confidence: 80%

“…Metformin is not metabolized in the body, oral bioavailability reaches 50 to 60%, and the rest of the dose is excreted in the feces (Tucker et al, 1981;Wiernsperger, 1996). Due to the biguanide chemical properties of metformin, the drug is characterized by a unique distribution behavior; following intraduodenal (or oral) administration, part of the metformin is reversibly adsorbed to the luminal surface of the intestinal wall (Hermann and Melander, 1992).…”

Section: Stepensky Et Almentioning

confidence: 99%

“…The glucose-lowering effect of metformin is apparently composed of a combination of several distinct activities in various organs and tissues (Hermann and Melander, 1992;Cusi and DeFronzo, 1998), including: 1) decreased hepatic glucose output due to decreased hepatic gluconeogenesis and increased glycogenesis and lipogenesis (Christiansen and Hellerstein, 1998); 2) reduced rate of intestinal glucose absorption (Wilcock and Bailey, 1991); and 3) increased glucose uptake by muscle cells and adipocytes (Bailey et al, 1996). The multifactorial mechanism of action of metformin and the complex nature of glucose homeostasis in vivo obscures the dose-response relationship of the metabolic effects in individual organs and tissues (Wiernsperger, 1996). As a result, the relative significance of the above-mentioned sites of metformin action (biophases) to produce metabolic effects remains unknown and is still a matter of continuous debate Abbasi et al, 1998;Cusi and DeFronzo, 1998).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetic-Pharmacodynamic Analysis of the Glucose-Lowering Effect of Metformin in Diabetic Rats Reveals First-Pass Pharmacodynamic Effect

Stepensky

Friedman²,

Raz³

et al. 2002

Drug Metabolism and Disposition

118

View full text Add to dashboard Cite

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Metformin, a commonly used antidiabetic drug, exerts its glucoselowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.Metformin, a biguanide glucose-lowering agent, is commonly used for management of type 2 diabetes. Despite the wide clinical use of metformin, the mechanism of its action is not fully understood. The glucose-lowering effect of metformin is apparently composed of a combination of several distinct activities in various organs and tissues (Hermann and Melander, 1992;Cusi and DeFronzo, 1998), including: 1) decreased hepatic glucose output due to decreased hepatic gluconeogenesis and increased glycogenesis and lipogenesis (Christiansen and Hellerstein, 1998); 2) reduced rate of intestinal glucose absorption (Wilcock and Bailey, 1991); and 3) increased glucose uptake by muscle cells and adipocytes (Bailey et al., 1996). The multifactorial mechanism of action of metformin and the complex nature of glucose homeostasis in vivo obscures the dose-response relationship of the metabolic effects in individual organs and tissues (Wiernsperger, 1996). As a result, the relative significance of the above-mentioned sites of metformin action (biophases) to produce metabolic effects remains unknown and is still a matter ...

show abstract

Section: Pk-pd Analysis Of Metforminsupporting

confidence: 80%

Section: Stepensky Et Almentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic-Pharmacodynamic Analysis of the Glucose-Lowering Effect of Metformin in Diabetic Rats Reveals First-Pass Pharmacodynamic Effect

Stepensky

Friedman²,

Raz³

et al. 2002

Drug Metabolism and Disposition

118

View full text Add to dashboard Cite

show abstract

“…etformin (Met) has been used as an oral pharmacological agent in the treatment of patients with type 2 diabetes for the past 40 years (1). Recently, it has been strongly suggested that its primary action is in the improvement of insulin sensitivity of the liver, resulting in a decrease in basal endogenous glucose production (2)(3)(4)(5).…”

mentioning

confidence: 99%

Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet

Mithieux

Guignot

Bordet³

et al. 2002

Diabetes

View full text Add to dashboard Cite

The aim of this study was to understand by which intrahepatic mechanism metformin (Met) may inhibit basal hepatic glucose production (HGP) in type 2 diabetes. We studied rats that were fed for 6 weeks a high-fat (HF) diet, supplemented (HF-Met) or not (HF) with Met (50 mg ⅐ kg ؊1 ⅐ day ؊1 ). Basal HGP, assessed by 3-[ 3 H]glucose tracer dilution, was lower by 20% in HFMet rats compared with HF-rats: 41.6 ؎ 0.7 vs. 52 ؎ 1.5 mol ⅐ kg ؊1 ⅐ min ؊1 (means ؎ SE, n ‫؍‬ 5; P < 0.01). Glucose-6 phosphatase (Glc6Pase) activity, assayed in a liver lobe freeze-clamped in situ, was lower by 25% in HF-Met rats compared with HF-rats (7.9 ؎ 0.4 vs. 10.3 ؎ 0.9 mol ⅐ min ؊1 ⅐ g ؊1 wet liver; P < 0.05). Glucose-6 phosphate and glycogen contents, e.g., 42 ؎ 5 nmol/g and 3.9 ؎ 2.4 mg/g, respectively, in HF-rats were dramatically increased by three to five times in HF-Met rats, e.g., 118 ؎ 12 nmol/g and 19.6 ؎ 4.6 mg/g (P < 0.05 and P < 0.01, respectively). Glucose-6 phosphate dehydrogenase activity was increased in HF-Met compared with HF rats (1.51 ؎ 0.1 vs. 1.06 ؎ 0.08 mol ⅐ min ؊1 ⅐ g ؊1 ; P < 0.01). Intrahepatic lactate concentration tended to be lower in the Met-group (؊30%; NS), whereas plasma lactate concentration was higher in HF-Met rats (1.59 ؎ 0.15 mmol/l) than in HF rats (1.06 ؎ 0.06 mmol/l; P < 0.05). We concluded that Met decreases HGP in insulin-resistant HF-fed rats mainly by an inhibition of hepatic Glc6Pase activity, promoting glycogen sparing. Additional mechanisms might involve the diversion of glucose-6 phosphate into the pentose phosphate pathway and an inhibition of hepatic lactate uptake. Diabetes 51:139 -143, 2002

show abstract

“…The ability of metformin to lower blood glucose concentration via a decrease in hepatic glucose production is predominantly attributed to an improvement of the peripheral tissue sensitivity to insulin [1,2]. However, and despite its widespread use, the mechanism of metformin action still remains poorly understood at the cellular level.…”

mentioning

confidence: 99%

Potentiating effect of metformin on insulin-induced glucose uptake and glycogen metabolism within Xenopus oocytes

1998

View full text Add to dashboard Cite

The potent anti-diabetic biguanide metformin is an oral antihyperglycaemic drug that is extensively used in the treatment of diabetes mellitus. The ability of metformin to lower blood glucose concentration via a decrease in hepatic glucose production is predominantly attributed to an improvement of the peripheral tissue sensitivity to insulin [1,2]. However, and despite its widespread use, the mechanism of metformin action still remains poorly understood at the cellular level.Recent advances in the understanding of molecular mechanisms underlying the process of insulin signalling allowed to specify better some metabolic actions of the biguanide. Results from studies on various insulin-sensitive cells or tissues explained the efficiency of metformin as a potentiation of hormonal action [3]. This partly proceeded from glucose uptake through a stimulatory effect associated with either an enhanced recruitment of responsive transporters such as GLUT4 or a change in the affinity of carriers [4]. Moreover, metformin acted on different biochemical pathways linked to the main metabolic functions of insulin, namely the lipid [5] and protein synthesis [6] as well as the carbohydrate metabolism [7,8].However, instead of using target somatic cells such as hepatocytes or adipocytes, another approach to characterize the synergism between metformin and insulin is the application of the Xenopus laevis oocyte as an experimental tool. This kind of cell, by its large amount of stored substances including glycogen and by other physiological features, provides an attractive model to elucidate the possible involvement of metformin in two major biological processes initiated by insulin, i. e. cell maturation and glycogen metabolism. Grigorescu and colleagues [9] were the first to observe that treatment with metformin potentiated the Diabetologia (1998) Summary Xenopus laevis oocytes were chosen as the in vitro model for this study with the aim of reconsidering metformin action on the main insulin-responsive glucose pathway. Metformin alone, when present at a therapeutic dose (20 mmol/l) in the incubation medium, did not alter the basal rate of glucose uptake or of glycogen synthesis as measured by [U-14 C] Dglucose incorporation. The drug had no effect on the main rate-limiting enzyme implicated in this pathway, i. e. glycogen synthase. In contrast, when combined with 2 mmol/l insulin, metformin led to a specific rise of both free and stored glucose, by 42.4 and 102.3 % respectively. Moreoever, a short-term preincubation of mature oocytes with metformin, but in the absence of glucose, enhanced significantly the amount of synthase a when stimulated by 50 nmol/l insulin (basal 17.4 ± 5.7 %, metformin 21.3 ± 4.1 %, insulin 31.2 ± 4.6 %, metformin together with insulin 62.7 ± 4.2 %, p < 0.005, n = 5). Interestingly, the microinjection of this biguanide, at a final concentration of 20 nmol/l, allowed a similar biochemical response. These data clearly suggest that metformin could act primarily at postreceptor steps which are thought to be ...

show abstract

Preclinical Pharmacology of Biguanides

Cited by 31 publications

References 147 publications

Pharmacokinetic-Pharmacodynamic Analysis of the Glucose-Lowering Effect of Metformin in Diabetic Rats Reveals First-Pass Pharmacodynamic Effect

Pharmacokinetic-Pharmacodynamic Analysis of the Glucose-Lowering Effect of Metformin in Diabetic Rats Reveals First-Pass Pharmacodynamic Effect

Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet

Potentiating effect of metformin on insulin-induced glucose uptake and glycogen metabolism within Xenopus oocytes

Contact Info

Product

Resources

About