Interaction of Organic Anion Transporter 3-Mediated Uptake of Steviol Acyl Glucuronide, a Major Metabolite of Rebaudioside A, with Selected Drugs.

Organic anion transporter 3 (OAT3) plays a critical role in the renal excretion of many xenobiotics. Because steviol acyl glucuronide (SVAG), an OAT3 substrate, is the major circulating metabolite after oral ingestion of steviol glycosides and is excreted into the urine, inhibition of OAT3 activity may alter pharmacokinetic profiles of SVAG. The present study showed that drugs such as probenecid and glimepiride displayed potent inhibition toward the OAT3-mediated SVAG transport, with IC values of 4.

CYP2C8-mediated interaction between repaglinide and steviol acyl glucuronide: In vitro investigations using rat and human matrices and in vivo pharmacokinetic evaluation in rats.

CYP2C8 is involved in the metabolic clearance of several important drugs and recent reports have shown that acyl glucuronides of gemfibrozil and clopidogrel are potent time-dependent inhibitors of CYP2C8 activity. In the present study, the inhibitory effect of steviol acyl glucuronide (SVAG), a circulating metabolite formed after the ingestion of rebaudioside A, was investigated using in vitro and in vivo systems. Results indicated that SVAG was a reversible but not a time-dependent inhibitor of CYP2C8-mediated paclitaxel 6α-hydroxylation.

Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation.

The prodrug strategy has been explored frequently for a number of marked drugs to obtain better pharmaceutical properties and efficacy and safety profiles. For gemcitabine, a nucleoside analog that has been used widely as a chemotherapeutic agent for the treatment of a variety of cancers, the protection of the amino group from extensive deamination and increase of permeability have been used for oral prodrug development. In the present study, several novel and proprietary monophosphate ester prodrugs of gemcitabine representing different "tail" structures were evaluated for their antiproliferation activities in various tumor cell lines.

Metabolic Interaction Potential between Clopidogrel and Sulfonylurea Antidiabetic Agents: Effects on Clopidogrel Bioactivation.

Background: Patients with diabetes have increased rates of cardiovascular events, and concomitant use of antidiabetic agents and clopidogrel may increase the risk for drug interactions. This study was undertaken to investigate the interaction potential between sulfonylurea drugs and clopidogrel, with an emphasis on key steps in the clopidogrel bioactivation processes.

Methods: Inhibition of clopidogrel metabolism by sulfonylureas was evaluated by monitoring the formation of clopidogrel carboxylic acid and 2-oxo-clopidogrel in human liver microsomes (HLM), human intestinal microsomes and recombinant human enzymes.

Transmembrane transport of steviol glucuronide and its potential interaction with selected drugs and natural compounds.

Steviol glucuronide (SVG) is the major metabolite derived from steviol, the aglycone of stevioside and rebaudioside A. After the ingestion of stevioside and rebaudioside A, SVG is formed and excreted into the urine in humans. In the present study, transporter mediated efflux and uptake of SVG was investigated in order to understand molecular mechanisms underlying its renal clearance.