%0 Journal Article %A Kirk D. Kozminski %A Jangir Selimkhanov %A Scott Heyward %A Michael A. Zientek %T Contribution of extra-hepatic aldehyde oxidase activity to human clearance %D 2021 %R 10.1124/dmd.120.000313 %J Drug Metabolism and Disposition %P DMD-AR-2020-000313 %X Aldehyde oxidase (AOX) is a soluble, cytosolic enzyme that metabolizes various N-heterocyclic compounds and organic aldehydes. It has wide tissue distribution with highest levels found in liver, kidney, and lung. Human clearance projections of AOX substrates by in vitro assessments in isolated liver fractions (cytosol, S9) and even hepatocytes have been largely under-predictive of clinical outcomes. Various hypotheses have been suggested as to why this is the case. One explanation is that extra-hepatic AOX expression contributes measurably to AOX clearance and is at least partially responsible for the often observed under-predictions. Although AOX expression has been confirmed in several extra-hepatic tissues, activities therein and potential contribution to overall human clearance have not been thoroughly studied. In this work, the AOX enzyme activity using the S9 fractions of select extra-hepatic human tissues (kidney, lung, vasculature, and intestine) were measured using carbazeran as a probe substrate. Measured activities were scaled to a whole-body clearance using best-available parameters and compared to liver S9 fractions. Here, the combined scaled AOX clearance obtained from the kidney, lung, vasculature and intestine is very low and amounted to <1% of liver. This work suggests that AOX metabolism from extra-hepatic sources plays little role in the underprediction of activity in human. One of the notable outcomes of this work has been the first direct demonstration of AOX activity in human vasculature. Significance Statement This work demonstrates AOX activity is measurable in a variety of extra-hepatic human tissues, including vasculature, yet activities and potential contributions to human clearance are relatively low and insignificant when compared to the liver. Additionally, the modeling of the tissue specific in vitro kinetic data suggests that AOX may be influenced by the tissue it resides in and thus show different affinity, activity, and modified activity over time. %U https://dmd.aspetjournals.org/content/dmd/early/2021/06/23/dmd.120.000313.full.pdf