In Vitro-In Vivo Correlation for Intrinsic Clearance for Drugs Metabolized by Human Aldehyde Oxidase

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 develop in vitro-in vivo correlations of clearance, differ from humans 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 11 drugs known to be metabolized by this enzyme. The set consisted of methotrexate, XK-469, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine (RS-8359), zaleplon, 6-deoxypenciclovir, zoniporide, O-6-benzylguanine, N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (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 they were then compared with 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 that is metabolized by this enzyme will possess acceptable human clearance, or when structural modification is required to reduce aldehyde oxidase catalyzed metabolism.