Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3

Flavin-containing monooxygenase 3 (FMO3) is an important hepatic enzyme for the detoxification of xenobiotics. The pharmacogenetic relevance of FMO3 deficiency has frequently been postulated from in vitro studies but has not yet been proven in vivo. We investigated the metabolism of benzydamine (BZD) in controls as well as patients with severe FMO3 deficiency and found evidence of markedly reduced N-oxygenation capacity both in serum and urine samples. After 2 h the N-oxide/total BZD ratio in serum of the patients ranged from 3.1 to 5.6% compared to controls with a median of 13.1%. Urinary BZD was almost fully N-oxygenated in controls (>93.7%) whilst the urinary N-oxide/total BZD ratios were 29.4-35.7% in patients. Our study is the first to confirm that severe FMO3 deficiency is associated with reduced metabolism of a drug substrate in vivo. This is relevant because of the prevalence of mild FMO3 deficiency in the general population. BZD may be also useful as a diagnostic probe for determination of FMO3 deficiency in vivo. (C) 2004 Lippincott Williams Wilkins.