Prolonged blood glucose reduction in mrp-2 deficient rats (GY/TR(-)) by the glucose-6-phosphate translocase inhibitor S 3025.
Chlorogenic acid derivatives are potent inhibitors of hepatic glucose production by inhibition of the glucose-6-phosphate translocase component of the hepatic glucose-6-phosphatase system. The pharmacological proof of concept was clearly demonstrated during i.v. infusion of potent derivatives (S 4048, S 3483) in rats. However, the blood glucose lowering effect of S 4048 after bolus i.v. injection lasted only 60-90 min. Plasma clearance of S 4048 was very high, and the parent compound was rapidly and efficiently excreted into the bile of Wistar and GY/TR(-) rats, indicating that mrp-2 was not involved in this hepatobiliary elimination process. About 72% of the total administered radioactivity appeared in the bile within 20 min after i.v. bolus injection of the radiolabeled analogue [(3)H]S 1743 in a Wistar rat. However, in GY/TR(-) rats the dicarboxylic analogue of S 4048, S 3025, was cleared from the plasma less rapidly than its parent compound and its biliary elimination was comparatively low. In contrast, S 3025 exhibited comparable pharmacokinetics and biliary elimination profile as S 4048 in Wistar rats, suggesting that biliary elimination of S 3025 is facilitated by mrp-2, functionally absent in GY/TR(-) rats. Targeting to mrp-2 resulted in a significantly prolonged reduction of blood glucose levels in GY/TR(-) rats after i.v. bolus administration of S 3025.
Herling
Andreas W
AW
Aventis Pharma Deutschland GmbH, H 821 Pharmacology, 65926 Frankfurt am Main, Germany. andreas.herling@aventis.com
Schwab
Dietmar
D
Burger
Hans-Joerg
HJ
Maas
Jochen
J
Hammerl
Roland
R
Schmidt
Dietmar
D
Strohschein
Sabine
S
Hemmerle
Horst
H
Schubert
Gerrit
G
Petry
Stefan
S
Kramer
Werner
W
D000818:Animals; D017920:Antiporters; D001646:Bile / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis*; D019742:Chemokines, CC; D016207:Cytokines / Q000172:deficiency*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D007093:Imidazoles / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D019402:Macrophage Inflammatory Proteins; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium
D017920:Antiporters; D001786:Blood Glucose; C095218:Ccl9 protein, mouse; D019742:Chemokines, CC; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019402:Macrophage Inflammatory Proteins; D009004:Monosaccharide Transport Proteins; D011725:Pyridines; C454799:S 3025; C403582:S 4048; C503532:Slc37a4 protein, mouse; C503533:Slc37a4 protein, rat; C111261:glucose 6-phosphate(transporter); D014316:Tritium; D010770:Phosphotransferases