Fluorinated drug metabolism in microorganisms
The presence of fluorine in a pharmaceutical compound can have a profound effect on its bioactivity, stability and lipophilicity, and it is unsurprising that this element is increasingly used in drug design with approximately 25 percent of new commercially available pharmaceuticals containing fluorine atoms. In this paper the application of microorganisms, such as Bacillus, Streptomyces bacteria, and Cunninghamella fungi, in modelling fluorinated drug metabolism in mammals is discussed. The ready scalability of these microbial cultures also provides a platform for the production of drug metabolites for in vitro testing, which is likely to be increasingly important following the US FDA’s recent MIST (Metabolites in Safety Testing) guidelines. Furthermore, microorganisms might be employed to identify optimum sites for selective fluorination in iterative drug design.
MICROORGANISMS AS MODELS OF MAMMALIAN DRUG METABOLISM
Smith and Rosazza (1) first recognised the potential of microorganisms to mimic mammalian metabolism of pharmaceuticals and drugs. Subsequent studies revealed that some microorganisms have analogous enzymes to those involved in oxidative (phase I) and conjugative (phase II) detoxification pathways in mammals (2, 3). This raised the possibility of microorganisms being used in the assessment of toxicity during drug development, potentially replacing animals, and in the production of drug metabolites, since microorganisms are readily scalable. However, as the understanding of the main class of enzyme, cytochromes P450 (CYPs), involved in oxidative transformation of drugs has developed, it has become clear that although microbial CYPs can transform a wide range of drugs, they often yield a different metabolite profile to mammals (4). Subsequently, the advancements in ‘humanised’ technology makes it is possible to use hepatocytes and liver microsomes as more appropriate models of human drug metabolism.
Owing to fluorine’s unique physicochemical prope ...