Role of flavin-containing monooxygenase in drug development.
This review summarizes some recent observations and information related to the role of the flavin-containing monooxygenase (FMO) in preclinical drug development. Flavin-containing monooxygenase is a complimentary enzyme system to the cytochrome P450 (CYP) family of enzymes and oxygenates several soft, highly polarizable nucleophilic heteroatom-containing chemicals and drugs. The products of FMO-mediated metabolism are generally benign and highly polar, readily excreted materials. There may be some advantages in designing drugs that are metabolized in part by FMO and not exclusively by CYP. In this review, I describe the practical aspects for the participation of FMO in drug and chemical metabolism including: i) the study of FMO using in vitro preparations; ii) some observations about metabolism of drugs and chemicals by FMO in vivo; and iii) the consequences of studying FMO-related metabolism in various small animal models. Some of the preclinical research and development areas related to FMO are not fully mature areas and there are certain gaps in our knowledge. However, I include discussion of these areas to stimulate further work and invite further discussion.
Cashman
John R
JR
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA. JCashman@HBRI.org
D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D010105:Oxygenases / Q000378:metabolism*
D015507:Drugs, Investigational; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)