36504-71-9Relevant articles and documents
Functional assessment of rat pulmonary flavin-containing monooxygenase activity
Yilmaz, Yildiz,Williams, Gareth,Manevski, Nenad,Walles, Markus,Kr?henbühl, Stephan,Camenisch, Gian
, p. 1 - 10 (2018)
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.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.The predicted lung clearance (CLlung) 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 CLlung using rat lung microsomes corresponded to approximately 35% of rat CLliver suggesting that the lung makes a smaller contribution to the whole body clearance of benzydamine.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.
Human flavin-containing monooxygenase 3 on graphene oxide for drug metabolism screening
Castrignanò, Silvia,Gilardi, Gianfranco,Sadeghi, Sheila J.
, p. 2974 - 2980 (2015)
Human flavin-containing monooxygenase 3 (hFMO3), a membrane-bound hepatic protein, belonging to the second most important class of phase-1 drug-metabolizing enzymes, was immobilized in its active form on graphene oxide (GO) for enhanced electrochemical response. To improve protein stabilization and to ensure the electrocatalytic activity of the immobilized enzyme, didodecyldimethylammonium bromide (DDAB) was used to mimic lipid layers of biological membranes and acted as an interface between GO nanomaterial and the hFMO3 biocomponent. Grazing angle attenuated total reflectance Fourier transform infrared (GATR-FT-IR) experiments confirmed the preservation of the protein secondary structure and fold. Electrochemical characterization of the immobilized enzyme with GO and DDAB on glassy carbon electrodes was carried out by cyclic voltammetry, where several parameters including redox potential, electron transfer rate, and surface coverage were determined. This systems biotechnological application in drug screening was successfully demonstrated by the N-oxidation of two therapeutic drugs, benzydamine (nonsteroidal anti-inflammatory) and tamoxifen (antiestrogenic widely used in breast cancer therapy and chemoprevention), by the immobilized enzyme.
Biotransformation of benzydamine by microsomes and precision-cut slices prepared from cattle liver
Santi,Anfossi,Coldham,Capolongo,Sauer,Montesissa
, p. 73 - 86 (2007/10/03)
1. Benzydamine (BZ), a non-steroidal anti-inflammatory drug used in human and veterinary medicine, is not licensed for use in food-producing species. Biotransformation of BZ in cattle has not been reported previously and is investigated here using liver microsomes and precision-cut liver slices. 2. BZ was metabolized by cattle liver microsomes to benzydamine N-oxide (BZ-NO) and monodesmethyl-BZ (Nor-BZ). Both reactions followed Michaelis-Menten kinetics (Km = 76.4 ± 16.0 and 58.9 ± 6.4 μM, Vmax = 6.5 ± 0.8 and 7.4 ?? 0.5 nmol mg-1 min-1, respectively); sensitivity to heat and pH suggested that the N-oxidation is catalysed by the flavin-containing monooxygenases. 3. BZ-NO and Nor-BZ were the most abundant products derived from liver slice incubations, and nine other BZ metabolites were found and tentatively identified by LC-MS. Desbenzylated and hydroxylated BZ-NO analogues and a hydroxylated product of BZ were detected, which have been reported in other species. Product ion mass spectra of other metabolites, which are described here for the first time, indicated the formation of a BZ N+-glucuronide and five hydroxylated and N+-glucuronidated derivatives of BZ, BZ-NO and Nor-BZ. 4. The results indicate that BZ is extensively metabolized in cattle. Clearly, differences in metabolism compared with, for example, rat and human, will need to be considered in the event of submission for marketing authorization for use in food animals.
