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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. As compared to LY2334737, a prototype oral prodrug of gemcitabine, the monophosphate ester prodrugs exhibited superior in vitro antiproliferation activity. Among those, compound-3 emerged as a promising prodrug candidate. Data revealed that cellular concentrations of compound-3 were correlated well with its antiproliferation activity and its cellular uptake did not involve human equilibrative nucleoside transporter, suggesting a potential to treat gemcitabine resistant tumors. Compound-3 demonstrated equal or better antitumor efficacy after oral administration as compared to intraperitoneally injected gemcitabine. Taken together, compound-3 has the potential for further development as an orally active antitumor agent.

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 50 values of 4.9 and 0.8 μM, respectively. No species differences were observed. Probenecid and glimepiride could significantly elevate plasma concentrations of SVAG after oral administration of rebaudioside A, with significant increases in plasma maximum (C max ) and area under the plasma time−concentration curve values. The inhibitory effect on the OAT3mediated SVAG transport exemplified a unique case between drugs and the metabolite of a food additive. Our data suggest that caution should be exercised when giving steviol glycoside products to human subjects with compromised renal function.

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. CYP2C9-based interaction was investigated for both 2-oxo-clopidogrel and glimepiride using HLM and the recombinant CYP2C9 system. Results: For the formation of clopidogrel carboxylic acid (the deactivation step) and 2-oxo-clopidogrel (the first step of bioactivation) in human microsomes, the inhibition potency of the 3 sulfonylurea drugs tested followed the order of glimepiride > glipizide > gliclazide. For the metabolism of 2-oxo-clopidogrel (the second step of bioactivation), glimepiride demonstrated a relatively strong inhibition against CYP2C9 activity (IC₅₀ 12.7 μmol/l). In addition, 2-oxo-clopidogrel displayed a moderate inhibitory effect toward the CYP2C9-mediated metabolism of glimepiride. Conclusion: The moderate inhibition observed for clopidogrel bioactivation may not present a significant risk for drug-drug interactions between sulfonylureas and clopidogrel. While these findings bode well for multidrug therapies involving sulfonylureas and clopidogrel, clinical investigations are needed to define the clinical risk and benefit for combining these agents for the management of cardiovascular events in diabetic patients.