Pharmacokinetic and Pharmacodynamics Interaction between Syzygium cumini and Glipizide: Role of Cytochrome P450 Enzyme

Abstract:

Background: Concomitant administration of herbs and synthetic drugs causes pharmacokinetic and pharmacodynamic interactions. Objectives: To investigate pharmacokinetic and pharmacodynamic interactions between Syzygium cumini (S. cumini, SC) and Glipizide (GZ) and the role of cytochrome P450 (CYP) enzymes in interaction. Methods: The effect of the aqueous seed extract of S. cumini (50 and 100 μg) on CYP3A was studied using in vitro liver microsomes. The interaction of GZ, a second-generation sulphonylurea, with S. cumini was examined in Sprague Dawley rats with type 2 diabetes induced through the administration of a high-fat diet, followed by Streptozotocin (STZ) injection. We administered 5mg/kg GZ and 250 and 400 mg/kg S. cumini seeds aqueous extract orally. Pharmacodynamic parameters were evaluated by analysing blood glucose, Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) and Alkaline Phosphatase (ALP) levels and by conducting the oral glucose tolerance test. The pharmacokinetics of GZ in combination with S. cumini was studied on the 14th day of treatment. Plasma levels were determined through LCMS at various time points (1, 2, 4, 8 and 12 hr after oral administration). Results: The hypoglycaemic effect exerted by the combination of GZ and S. cumini was significantly higher than that exerted by GZ and S. cumini administered alone but not below the normal level. Treatment with GZ and S. cumini caused a significant changein ALT and ALP levels compared with treatment with GZ alone. Pre-treatment with S. cumini increased the AUC of GZ, which could be due to CYP3A inhibition observed in in-vitro analysis. Conclusion: Pharmacokinetic and pharmacodynamic interactions occur between S. cumini and GZ.

Key words: Herb–drug interactions, Type 2 diabetes mellitus, Pharmacokinetics, LCMS, CYP3A.