Quinone Imines

Phenacetin is a classical example of a quinone imine, with oxidation of the compound by cytochrome P450 leading to a benzoquinone intermediate (Figure 8.8). The benzoquinone reacts with various cytosolic proteins to trigger direct hepatotoxi-

Toxicity by metabolism is not confined to the liver since oxidative systems occur in many organs and cells. Amodiaquine is a 4-aminoquinoline antimalarial that has been associated with hepatitis and agranulocytosis. Both side-effects are probably triggered by reactive metabolites produced in the liver or in other sites of the body. For instance polymorphonuclear leucocytes can oxidize amodiaquine. It appears that amodiaquine is metabolized to a quinone imine by the same pathway as that seen in

Fig. 8.8 Oxidation of phenacetin to a benzoquinone intermediate.

Fig. 8.8 Oxidation of phenacetin to a benzoquinone intermediate.

the case of acetaminophen [11] (Figure 8.9), suggesting that such structural features in a molecule should be avoided.

Such reactions can occur in other molecules containing aromatic amine functions without a para oxygen substituent. For instance diclofenac can be oxidized to a minor metabolite (5-OH) diclofenac which can be further oxidized [12] to the benzoqui-nine imine metabolite (Figure 8.10). Again, the reactivity of this intermediate has been implicated in the hepatotoxicity of the compound.

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11).

Indomethacin is associated, in the clinic, with a relatively high incidence of agranulocytosis. Although indomethacin itself is not oxidized to reactive metabolites, one of its metabolites, dsemethyldeschlorobenzoylindomethacin (DMBI) forms an imi-noquinone [14]. Formation of the iminoquinone from DMBI is catalysed by

Fig. 8.10 Scheme showing metabolism of diclofenac by oxidation (A) to benzoquinone imine (C) metabolites.
Fig. 8.11 Metabolism of tacrine to hydroxyl metabolites, the 5-hydroxy derivative of which can be further oxidized to the reactive quinone imine.

myeloperoxidase (the major oxidizing enzyme in neutrophils) and HOCl (the major oxidant produced by activated neutrophils). The pathway for formation of the imino-quinone is illustrated in Figure 8.12.

Practolol (Figure 8.13) was the prototype cardioselective p-adrenoceptor blocking agent. Selectivity was achieved by substitution in the para position with an acetyl anilino function. The similarity of this drug with those outlined above is obvious. Practolol caused severe skin and eye lesions in some patients which led to its withdrawal from the market [6]. These lesions manifested as a rash, hyperkeratosis, scarring, even perforation of the cornea and development of a fibrovascular mass in the conjunctiva, and sclerosing peritonitis. Some evidence is available that the drug is oxidatively metabolized to a reactive product that binds irreversibly to tissue pro

Fig. 8.13 Structures of practolol and atenolol. practolol teins. That the toxic functionality is the acetanilide is confirmed by the safety of a follow-on drug atenolol. Atenolol (Figure 8.13) has identical physicochemical properties and a very similar structure except that the acetyl-amino function has been replaced with an amide grouping. This structure cannot give rise to similar aromatic amine reactive metabolites. The withdrawal of practolol from the market is obviously a severe blow to the manufacturer and to those patients who benefited from it. Although not shown to be the cause of toxicity the presence of an aromatic amine in the structure of nomifensine (Figure 8.14) has to be treated with suspicion, the compound was also withdrawn from the market 9 years after its launch due to a rising incidence of acute immune haemolytic anaemia [15].

Carbutamide was the first oral anti-diabetic, and the prototype for the sul-phonamide type of agent. Carbutamide caused marked bone marrow toxicity in man, but derivatives of this, not containing the anilino function, such as tolbutamide

Fig. 8.15 Structures of carbutamide an oral anti-diabetic, associated with bone marrow toxicity, and tolbutamide a compound without similar effects.

(Figure 8.15), were devoid of such toxicity. As for many of the agents featured in this section the structural similarity between carbutamide and tolbutamide clearly implicates the anilino function as the toxicophore.

Fig. 8.16 Structures of Na+ channel blocker antiarrythmics: lidocaine (A), procaineamide (B), tocainide (C) and flecainide (D).

A further example of the design of drugs to remove aromatic amine functionalities even when present as a amide, is illustrated by the Na+ channel class of antiarrhythmic drugs [16]. Lidocaine is very rapidly metabolized (Figure 8.16) and so is only useful as a short-term intravenous agent. Oral forms include procainamide, tocainide and flecainide (Figure 8.16). Procainamide causes fatal bone marrow aplasis in 0.2 % of patients and lupus syndrome in 25-50 %. Tocainide also causes bone marrow aplasis and pulmonary fibrosis. In contrast, flecainide, whose structure contains no aromatic amine, masked or otherwise, has adverse effects related directly to its pharmacology. Interestingly, the lupus syndrome seen with procainamide is largely absent when N-acetyl procainamide is substituted.

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