Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice.
1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide. 3. Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high. 4. The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.
a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan.
Miho
M
Yamazaki-Nishioka
a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan.
Makiko
M
Shimizu
b Laboratory Animal Research Department , Central Institute for Experimental Animals , Kawasaki-ku , Japan , and.
Hiroshi
H
Suemizu
b Laboratory Animal Research Department , Central Institute for Experimental Animals , Kawasaki-ku , Japan , and.|c Technical Service Department, CLEA Japan, Inc , Fujinomiya , Japan.
Megumi
M
Nishiwaki
a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan.
Marina
M
Mitsui
a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan.
Hiroshi
H
Yamazaki
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism*; D001591:Benzydamine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D006801:Humans; D055442:Metabolome; D051379:Mice; D010105:Oxygenases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C048872:benzydamine N-oxide; D001591:Benzydamine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)
FMO; PBPK modeling; TK-NOG mice; kidney; liver; species differences