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FIGURE 8 Prodrugs of quinolone agents.

this nucleus. The structurally related tosufloxacin requires twice-daily dosing, however, emphasizing the contribution of trovafloxacin's azabicyclo[3.1.0]hex-ane sidechain. In keeping with the information described, trovafloxacin is judged to be a relatively lipophilic quinolone by its distribution coefficient [109]. Further support for the importance of the 8-position is the fact that C-8 halogens have also been noted to improve in vivo activity [23].


Phototoxicity is one of the clearest examples of the effect of structure on the biological activity of quinolone agents. Introduction of halogen atoms (fluorine or chlorine) at the C-8 position of the quinolone nucleus results in compounds with an enhanced tendency to induce photosensitivity, both in humans and in animal models. In keeping with this SAR, substantial phototoxicity has been reported for fleroxacin, lomefloxacin, sparfloxacin, clinafloxacin, and BAY y 3118 [21,110,111].

In a number of the newer quinolones, the C-8 halogens have been abandoned in favor of a methoxy group at that position. This substituent also provides improved in vitro potency over the unsubstituted analogue (see the section on "Overall Potency"), but without the phototoxicity issues of the halogens [112]. In one example, the development of BAY y 3118 was discontinued, but the 8-methoxy analogue moxifloxacin was recently approved. Moxifloxacin and gatifloxacin have been reported to be free of phototoxicity [113,114]. Interestingly, it may not be merely removal of the halogen atom that results in an improvement in photostability. In vitro irradiation experiments with UV light have suggested that the 8-methoxy group in balofloxacin stabilizes the quinolone to degradation [115].

Theophylline Interactions

A number of quinolones have been shown to reduce the clearance of theophylline by inhibiting its cytochrome P450-mediated metabolism. The most significant interaction is seen with enoxacin. Ciprofloxacin, grepafloxacin, and tosufloxacin increase serum levels of theophylline also, but to a lesser extent [116,117].

No significant alteration of theophylline clearance has been seen in clinical trials with sparfloxacin, gatifloxacin, trovafloxacin, temafloxacin, moxifloxacin, levofloxacin, and balofloxacin [2,116-121]. It is notable that many of the C-8-substituted quinolones exhibit no effect on theophylline pharmacokinetics. This effect for 8-fluoro and 8-methoxy groups has been established in an SAR study [112], although in that work naphthyridones were implicated as problematic for theophylline interactions. Tosufloxacin fits this model, but again the bicyclic sidechain of trovafloxacin results in a change in activity, such that trovafloxacin does not affect theophylline pharmacokinetics. The presence of a 3-aminopyr-rolidine in tosufloxacin may contribute to the interaction, as clinafloxacin, which bears the same C-7 sidechain, has been reported to increase the AUC of theophylline by two- to threefold, despite the presence of an 8-substituent [123]. Gemifloxacin does not exhibit a theophylline interaction, even though it employs a naphthyridone nucleus [124]. This may be due to the steric encumbrance provided by the methyl oxime adjacent to the aminomethyl group (vide infra).

The effect of methylation on the amine sidechain is a subject of debate. Increased bulk around the distal amine has been cited as a method of decreasing theophylline interactions [21]; other workers [122] have found that the position and number of methyl groups on a C-7 piperazine have little effect. Although the methylpiperazine of grepafloxacin does not distinguish it from ciprofloxacin in terms of its theophylline effects, the dimethyl substitution on sparfloxacin may contribute to its lack of interaction. In the case of balofloxacin, the presence of the methyl group on the exocyclic amine was shown to decrease the theophylline interaction compared to an unsubstituted amino group [125]. This may extend to the aminopyrrolidine sidechain: while clinafloxacin exhibits a theophylline interaction (vide supra), the structurally similar sitafloxacin was reported to exhibit only a small increase in serum theophylline levels [126]. In this case, the spirocyclopropane adjacent to the amino group on the pyrrolidine C-7 substituent of sitafloxacin may ameliorate the theophylline interaction.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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