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Metabolism of AFQ056 (Mavoglurant) by Rat Pulmonary CYP1A1

Yilmaz, Yildiz and Williams, Gareth and Schiller, Hilmar and Faller, Thomas and Walles, Markus and Camenisch, Gian P. and Umehara, Ken-Ichi and Krähenbühl, Stephan and Manevski, Nenad (2017) Metabolism of AFQ056 (Mavoglurant) by Rat Pulmonary CYP1A1. Xenobiotica, Online. ISSN 0049-8254

Abstract

1. In vitro enzyme phenotyping results indicate that CYP1A1 is responsible for the formation of the oxidative metabolite, M3. In line with the predominant assumption that CYP1A1 is mainly expressed in extrahepatic tissues, only traces of M3 were detected in hepatic systems. The aim of this study was to investigate the pulmonary CYP1A1 mediated metabolism of AFQ056 in rat.
2. In vitro incubations were performed with recombinant rat CYP1A1, rat lung microsomes and rat lung tissue slices. In vivo pulmonary extraction was investigated by intravenous (pre-lung) and intra-arterial (post-lung) dosing of AFQ056 to rats. Lung microsomal and tissue slice data were used to predict AFQ056 lung clearance (CLlung).
3. M3 formation was observed in recombinant CYP1A1 enzyme, in lung microsomes and tissue slices. However, CLlung predicted using the well stirred model indicated that the lung clearance would be negligible (0.03 mL/min/kg, <1% pulmonary blood flow). This observation was confirmed by the in vivo experiments which failed to show significant pulmonary extraction.
4. While lung may make a contribution to the formation of M3, it is unlikely to be the only organ involved in this process and further experiments are required to investigate the potential metabolic elimination routes for AFQ056.

Item Type: Article
Date Deposited: 08 May 2018 00:45
Last Modified: 08 May 2018 00:45
URI: https://oak.novartis.com/id/eprint/33574

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