Fluorine hepatotoxicity

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

Metabolism of the anti-malarial amodiaquine provides quinone-imine, which is an electrophilic metabolite responsible for hepatotoxicity and agranulocytosis. These side effects have severely restricted the clinical use of amodiaquine. The replacement of the phenolic hydroxyl by a fluorine prevents from oxidation process. Then, the A/-dealkylation becomes the major process. This has led to further refinements, with the preparation of the A/-f-butyl analogue, a compound which resists towards metabolic side-chain cleavage and has an excellent in vitro and in vivo profile (Fig. 15) [56]. 

For about one hundred years, and longer in some parts of the world, diethyl ether and chloroform had no rivals. This was despite major drawbacks, the main ones being the flammability and slow onset of diethyl ether, and the hepatotoxicity and cardiac arrhythmias induced by chloroform. New discoveries in organic fluorine chemistry at the end of World War II paved the way for the synthesis of modern fluorinated anaesthetic alkanes and ethers. 

Enflurane is a fluorinated methyl ethyl ether and is a structural isomer of isoflurane (Figure 3.2). It was synthesised in 1963 and introduced into clinical practice in 1966 at a time when concern was growing about the hepatotoxicity of halothane. Its main advantage over halothane was its resistance to biotransformation (2.5% compared to some 20%). For that reason it was widely used as an alternative to halothane, particularly for multiple administration. 

This has been found to be the case with valproic acid (2-propylpentanoic acid) (12), which is hepatotoxic, and 2-fluorovalproic add (22), which is much less hepatotoxic, discussed in Sedion 4.3.1. The hepatoxidty of 12 involves cytochrome P450 abstraction of its C-2 hydrogen atom. The C-2 fluorine atom of 22 cannot be removed by cytochrome P450 metabolism. It would be interesting to observe if the same isosteric replacement would reduce the hepatoxidty of other carboxylic acids, such as the widely used 2-ethylhexanoic add. 

This patient had multiple risk factors for anesthesia-induced hepatitis, including obesity, middle age, female sex, a history of drug allergies, and multiple exposures to fluorinated anesthetic agents. Desflurane has a very low rate of hepatic oxidative metabolism (0.02 versus 20% for halothane), and is considered to be one of the safest volatile agents as far as hepatotoxicity is concerned. Nevertheless, this case shows that it can cause severe hepatotoxicity. 

Saperconazole is an experimental, water-insoluble, lipophilic, fluorinated triazole. Its structure resembles that of itraconazole and it has a long half-life. It has a broad antifungal spectrum, including Cryptococcus Species and Aspergillus species. In early studies in cases of compassionate use, only a few adverse effects were described, including hepatotoxicity (1,2), and its adverse effects were expected to resemble those of itraconazole (3). However, the manufacturers stopped developing it because of concerns about toxicity. 

Hepatitis following general anesthesia has been linked to use of halothane, though the incidence of severe hepatic necrosis is only about one out of 35,000 halothane administrations. The results of animal experiments suggest that halothane hepatotoxicity may be due to formation of a toxic metabolite produced under anoxic conditions. Hepatotoxicity has not been reported following desflurane administration it may be relevant that this agent is the least metabolized of the fluorinated hydrocarbons. All of the other statements are correct. The answer is (E). 

---