Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics

Abstract

Unacceptable pharmacokinetics (PK) relating to aldehyde oxidase (AO) metabolism have resulted in clinical failure of several promising drug candidates, yet reliable and standardized methods to predict the human PK and drug-drug interaction (DDI) liability of AO-metabolized drugs remains to be established. Investigations into the DDI liability associated with AO substrates also metabolized by cytochrome P450 and the potential utility of allometric scaling methods to predict human clearance (CL) of AO substrates were conducted. These investigations indicate a susceptibility of mixed AO/P450-metabolized drugs to DDI with P450 inhibitors, resulting in elevated AO metabolite exposure. In addition, data indicate allometric scaling with multiple or single species may be useful to predict human CL when appropriate species are utilized. Evaluations of biotransformation, fraction metabolized by AO (Fm,AO), hepatic extraction ratio (E), and allometric scaling of in vivo and in vitro CL indicate guinea pig and monkey may be most useful for single-species scaling, while minipig, rat, and mouse may also be of use in multispecies allometry.