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Key Words drug metabolism, drug toxicity, drug design, drug safety, defluorination, metabolic stability
Abstract This article reviews current knowledge of the metabolism of drugs that contain fluorine. The strategic value of fluorine substitution in drug design is discussed in terms of chemical structure and basic concepts in drug metabolism and drug toxicity.
INTRODUCTION
Fluorine substitution can alter the chemical properties, disposition, and biological activity of drugs (1). Many fluorinated compounds are currently widely used in the treatment of disease. These include antidepressants, antiinflammatory agents, antimalarial drugs, antipsychotics, antiviral agents, steroids, and general anaesthetics (2). The chemistry and medicinal chemistry of fluoro-organic compounds and drugs have been reviewed (1, 3-5). The development of new fluorinating agents has vastly increased the potential for synthesis of novel fluorinated drugs. In addition, the development of sophisticated noninvasive analytical techniques based on fluorine nuclear magnetic resonance (NMR) and positron emission topography has transformed the study of fluorinated drugs in man and animals (6-8).
The inclusion of a fluorine atom in a drug molecule can influence both the disposition of the drug and the interaction of the drug with its pharmacological target (Figure 1). For example, the effects of fluorine substitution on the interand intramolecular forces that affect binding of ligands, and thus introduce receptor subtype selectivity, at cholinergic and adrenergic receptors are now well understood (9-11). Fluorine substitution can also have a profound effect on drug disposition, in terms of distribution, drug clearance, route(s), and extent of drug metabolism (12). Such changes can be used constructively by medicinal chemists to improve both the safety and the efficacy of a drug. Therefore, the purpose of this review is twofold. First, to outline the chemical basis of changes in drug disposition that can be achieved by the introduction of fluorine. Second, to consider the pharmacological and toxicological implications of such changes with respect to drug response.
PHYSICOCHEMICAL PROPERTIES OF FLUORINATED DRUGS
The replacement of a hydrogen atom or hydroxyl group by a fluorine atom is a strategy widely used in drug development to alter biological function. Although it is generally thought that fluorine for hydrogen substitution causes minimal steric effects at receptor sites, the actual van der Waals radius of fluorine (1.47 Angstrom) lies between that of oxygen (1.57...