Functional assessment of rat pulmonary flavin-containing monooxygenase activity

Abstract

1. The expression of flavin-containing monooxygenase (FMO) varies extensively between human and commonly used preclinical species such as rat and mouse. The aim of this study was to investigate the pulmonary FMO activity in rat using benzydamine. Furthermore, the contribution of rat lung to the clearance of benzydamine was investigated using an in vivo pulmonary extraction model.

2. Benzydamine N-oxygenation was observed in lung microsomes and lung slices. Thermal inactivation of FMO and CYP inhibition suggested that rat pulmonary N-oxygenation is predominantly FMO mediated while any contribution from CYPs is negligible.

3. The predicted lung clearance (CL_lung) estimated from microsomes and slices was 16 ± 0.6 and 2.1 ± 0.3 mL/min/kg, respectively. The results from in vivo pulmonary extraction indicated no pulmonary extraction following intravenous and intra-arterial dosing to rats. Interestingly, the predicted CL_lung using rat lung microsomes corresponded to approximately 35% of rat CL_liver suggesting that the lung makes a smaller contribution to the whole body clearance of benzydamine.

4. Although benzydamine clearance in rat appears to be predominantly mediated by hepatic metabolism, the data suggest that the lung may also make a smaller contribution to its whole body clearance.

Keywords:

• Pulmonary metabolism
• flavin-containing monooxygenases (FMO)
• benzydamine
• rat pumonary FMO metabolism
• benzydamine noxygenation

Acknowledgements

The authors would like to acknowledge Jon Rose, Arnold Demailly, Gaelle Chenal, Hazel Smulders and Asadh Miah for their support in the generation of data.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Pharmacokinetic Sciences group at Novartis Institutes for Biomedical Research, Basel, Switzerland and Horsham, UK.