PT - JOURNAL ARTICLE AU - Klaus Gjervig Jensen AU - Anne-Marie Jacobsen AU - Christoffer Bundgaard AU - Dorrit Østergaard Nilausen AU - Zia Thale AU - Gamini Chandrasena AU - Martin Jørgensen TI - Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of <sup>14</sup>C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods AID - 10.1124/dmd.116.072793 DP - 2017 Jan 01 TA - Drug Metabolism and Disposition PG - 68--75 VI - 45 IP - 1 4099 - http://dmd.aspetjournals.org/content/45/1/68.short 4100 - http://dmd.aspetjournals.org/content/45/1/68.full SO - Drug Metab Dispos2017 Jan 01; 45 AB - Inclusion of a microdose of 14C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated.