zoniporide has been researched along with zaleplon* in 2 studies
2 other study(ies) available for zoniporide and zaleplon
Article | Year |
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Time Course of Aldehyde Oxidase and Why It Is Nonlinear.
Many promising drug candidates metabolized by aldehyde oxidase (AOX) fail during clinical trial owing to underestimation of their clearance. AOX is species-specific, which makes traditional allometric studies a poor choice for estimating human clearance. Other studies have suggested using half-life calculated by measuring substrate depletion to measure clearance. In this study, we proposed using numerical fitting to enzymatic pathways other than Michaelis-Menten (MM) to avoid missing the initial high turnover rate of product formation. Here, product formation over a 240-minute time course of six AOX substrates-O Topics: Acetamides; Acridines; Aldehyde Oxidase; Guanidines; Humans; Hydralazine; Kinetics; Liver; Nitroquinolines; Phthalazines; Pyrazoles; Pyrimidines; Reactive Oxygen Species | 2019 |
Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance.
Aldehyde oxidase (AO) metabolism could lead to significant underestimation of clearance in prediction of human pharmacokinetics as well as unanticipated exposure to AO-generated metabolites, if not accounted for early in drug research. We report a method using cryopreserved human hepatocytes and the time-dependent AO inhibitor hydralazine (K(I) = 83 ± 27 μM, k(inact) = 0.063 ± 0.007 min(-1)), which estimates the contribution of AO metabolism relative to total hepatic clearance. Using zaleplon as a probe substrate and simultaneously monitoring the AO-catalyzed formation of oxozaleplon and the CYP3A-catalyzed formation of desethyzaleplon in the presence of a range of hydralazine concentrations, it was determined that >90% inhibition of the AO activity with minimal effect on the CYP3A activity could be achieved with 25 to 50 μM hydralazine. This method was used to estimate the fraction metabolized due to AO [f(m(AO))] for six compounds with clearance attributed to AO along with four other drugs not metabolized by AO. The f(m(AO)) values for the AO substrates ranged between 0.49 and 0.83. Differences in estimated f(m(AO)) between two batches of pooled human hepatocytes suggest that sensitivity to hydralazine varies slightly with hepatocyte preparations. Substrates with a CYP2D6 contribution to clearance were affected by hydralazine to a minor extent, because of weak inhibition of this enzyme. Overall, these findings demonstrate that hydralazine, at a concentration of 25 to 50 μM, can be used in human hepatocyte incubations to estimate the contribution of AO to the hepatic clearance of drugs and other compounds. Topics: Acetamides; Aldehyde Oxidase; Cryopreservation; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Cytosol; Enzyme Activation; Hepatocytes; Humans; Hydralazine; Liver; Microsomes, Liver; Pyrimidines | 2012 |