Contribution of extra-hepatic aldehyde oxidase activity to human clearance
نویسندگان
چکیده
منابع مشابه
Hepatic Aldehyde Oxidase
Previous reports on rabbit liver aldehyde oxidase described the purification and some properties of the enzyme (1) and the differential inhibition of electron transfer to various acceptors (2). The latter study furnished evidence for the participation of several electron carriers in the internal electron transport sequence of the enzyme. The present communication summarizes the results of studi...
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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)), w...
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Human aldehyde oxidase (AO) is a molybdoflavoenzyme that commonly oxidizes azaheterocycles in therapeutic drugs. Although high metabolic clearance by AO resulted in several drug failures, existing in vitro-in vivo correlations are often poor and the extrahepatic role of AO practically unknown. This study investigated enzymatic activity of AO in fresh human skin, the largest organ of the body, f...
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Substrates of aldehyde oxidase (AO), for which human clinical pharmacokinetics are reported, were selected and evaluated in pooled mixed-gender cryopreserved human hepatocytes in an effort to quantitatively characterize AO activity. Estimated hepatic clearance (Cl(h)) for BIBX1382, carbazeran, O⁶-benzylguanine, zaleplon, and XK-469 using cryopreserved hepatocytes was 18, 17, 12, <4.3, and <4.3 ...
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The ability to predict in vivo clearance from in vitro intrinsic clearance for compounds metabolized by aldehyde oxidase has not been demonstrated. To date, there is no established scaling method for predicting aldehyde oxidase-mediated clearance using in vitro or animal data. This challenge is exacerbated by the fact that rats and dogs, two of the laboratory animal species commonly used to dev...
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ژورنال
عنوان ژورنال: Drug Metabolism and Disposition
سال: 2021
ISSN: 0090-9556,1521-009X
DOI: 10.1124/dmd.120.000313