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Publications (2)3.25 Total impact

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    ABSTRACT: Rufinamide was evaluated in vitro to determine which enzyme(s) are responsible for rufinamide hydrolysis and whether valproate, one of its metabolites (valproyl-CoA), and/or the rufinamide hydrolysis product (CGP 47292) could inhibit hydrolysis. Rufinamide hydrolysis was mediated primarily by human carboxylesterase (hCE) 1 and was nonsaturable up to 500 μM. Two-thirds of rufinamide hydrolysis was estimated to occur in human microsomes and one-third in cytosol. Valproate was a selective inhibitor for hCE1 compared to hCE2 and inhibition had a greater impact on rufinamide hydrolysis in microsomes than in cytosol. Valproyl-CoA caused similar inhibition of rufinamide hydrolysis in both microsomes and cytosol. Carboxylesterases were not significantly inhibited by CGP 47292. Inhibition of in vitro rufinamide hydrolysis by valproate could offer an explanation for the observed in vivo drug-drug interaction between the two antiepileptic drugs.
    No preview · Article · Oct 2011
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    ABSTRACT: Human carboxylesterase (CES) 1 and CES2 are members of the serine hydrolase superfamily, and both exhibit broad substrate specificity and are involved in xenobiotic and endobiotic metabolism. Although expression of CES1 and CES2 occurs in several organs, their expression in liver and small intestine is predominantly attributed to CES1 and CES2, respectively. We successfully expressed CES1 form b (CES1-b) and form c (CES1-c) as well as CES2 in baculovirus-infected High Five insect cells. With 4-nitrophenyl acetate (4-NPA) as the probe substrate, the K(m) values of recombinant CES1-b and CES2 matched those of human liver microsomes (HLM) and human intestinal microsomes (HIM) with approximately 200 and 180 μM, respectively. Bis(4-nitrophenyl) phosphate potently inhibited 4-NPA hydrolysis by HLM, CES1-b, CES1-c, HIM, and CES2 with IC(50) values less than 1 μM. With fluorescein diacetate (FD) as the substrate, the K(m) values were similar for all enzyme systems, with the exception of CES1-b, which was slightly lower; however, the V(max) values for HIM and CES2 were 39.5 and 14.6 μmol · mg(-1) · min(-1), respectively, which were at least 50-fold higher than those of CES1-b or CES1-c. Loperamide potently inhibited HLM, HIM, and CES2 with similar IC(50) values of approximately 1 μM. Substrate specificity was compared between human tissues and recombinant enzymes. The data suggest the following: 1) FD is a probe substrate for CES2; 2) CES1-b is the predominant form in human liver; and 3) recombinant CES1-b and CES2 expressed in insect cells are functionally consistent with native carboxylesterases expressed in human liver and intestine, respectively.
    Preview · Article · May 2011 · Drug metabolism and disposition: the biological fate of chemicals