PT  - JOURNAL ARTICLE
AU  - David Stepensky
AU  - Michael Friedman
AU  - Itamar Raz
AU  - Amnon Hoffman
TI  - Pharmacokinetic-Pharmacodynamic Analysis of the Glucose-Lowering Effect of Metformin in Diabetic Rats Reveals First-Pass Pharmacodynamic Effect
AID  - 10.1124/dmd.30.8.861
DP  - 2002 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 861--868
VI  - 30
IP  - 8
4099  - http://dmd.aspetjournals.org/content/30/8/861.short
4100  - http://dmd.aspetjournals.org/content/30/8/861.full
SO  - Drug Metab Dispos2002 Aug 01; 30
AB  - Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering 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. The American Society for Pharmacology and Experimental Therapeutics