RT Journal Article
SR Electronic
T1 <em>IN VITRO</em>-<em>IN VIVO</em> CORRELATION FOR INTRINSIC CLEARANCE FOR DRUGS METABOLIZED BY HUMAN ALDEHYDE OXIDASE
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.110.033555
DO 10.1124/dmd.110.033555
A1 Michael Zientek
A1 Ying Jiang
A1 Kuresh Youdim
A1 R. Scott Obach
YR 2010
UL http://dmd.aspetjournals.org/content/early/2010/05/05/dmd.110.033555.abstract
AB 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 by which a prediction of clearance mediated by aldehyde oxidase can be made 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 develop in vitro-in vivo correlations of clearance differ from human with regard to expression of aldehyde oxidase. The objective of this investigation was to develop an in vitro-in vivo correlation of intrinsic clearance for aldehyde oxidase, using eleven drugs known to be metabolized by this enzyme. The set consisted of methotrexate, XK-489, RS-8359, zaleplon, 6-deoxypenciclovir, zoniporide, O6-benzylguanine, DACA, carbazeran, PF-4217903 and PF-945863. These compounds were assayed using two in vitro systems, (pooled human liver cytosol and liver S-9 fractions) to calculate scaled unbound intrinsic clearance, and were then compared to calculated in vivo unbound intrinsic clearance. The investigation provided a relative scale that can be used for in vitro-in vivo correlation of aldehyde oxidase clearance and suggests limits as to when a potential new drug candidate which is metabolized by this enzyme will possess acceptable human clearance, or when structural modification is required to reduce aldehyde oxidase catalyzed metabolism.The American Society for Pharmacology and Experimental Therapeutics