Prolonged blood glucose reduction in mrp-2 deficient rats (GY/TR −) by the glucose-6-phosphate translocase inhibitor S 3025

• Published in: Biochimica et biophysica acta 2002-01, Vol.1569 (1), p.105-110
• Main Authors: Herling, Andreas W., Schwab, Dietmar, Burger, Hans-Joerg, Maas, Jochen, Hammerl, Roland, Schmidt, Dietmar, Strohschein, Sabine, Hemmerle, Horst, Schubert, Gerrit, Petry, Stefan, Kramer, Werner
• Format: Article
• Language: English
• Subjects: Animals; Antiporters; Bile - metabolism; Blood glucose; Blood Glucose - analysis; Chemokines, CC; Cytokines - deficiency; Down-Regulation; Enzyme Inhibitors - pharmacokinetics; Glucose-6-phosphate translocase; Hepatobiliary elimination; Imidazoles - pharmacokinetics; Infusions, Intravenous; Macrophage Inflammatory Proteins; Molecular Structure; Monosaccharide Transport Proteins; mrp-2; Phosphotransferases - antagonists & inhibitors; Pyridines - pharmacokinetics; Rats; Rats, Wistar; S 4048; Tritium
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/S0304-4165(01)00239-2

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 [ 3H]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.