Structure-Adverse Event Relationships
Unfortunately, phototoxicity will limit the clinical usefulness of several second-, third-, and fourth-generation quinolone agents. The introduction of a halogen (e.g., fluorine or chlorine) at the C-8 position of the 4-quinolone nucleus results in enhanced phototoxic potential in human and animal models.[29,30] Compounds that are limited by this substitution include lomefloxacin, sparfloxacin, fleroxacin, and clinafloxacin. Interestingly, compounds with an 8-methoxy substitution (e.g., gatifloxacin and moxifloxacin) have essentially no phototoxic potential, which may be due to stabilization of the quinolone to ultraviolet light degradation (Fig. 3E).[38,39,40,41]
The clinician should be cognizant that drugs and food additives can be modified by intestinal anaerobes. For instance, Eubacterium lentum, which is a gram-positive anaerobic bacilli constituent of the bowel flora, can reduce digoxin to an inactive form. Approximately 10% of the general population and up to 30% of urban populations have E. lentum as part of their fecal flora and typically require increased dosages of this agent. For this reason, the administration of antibiotics that have activity against this organism may result in up to a twofold increase in digoxin levels. Like macrolides and tetracyclines, quinolones as a class have activity against this bacterium.[44,45]
Morphine sulfate decreases the secretion of hydrochloric acid in the stomach by inhibition of the opioid receptors on parietal cells. Because of antagonism of these receptors, the pH of the stomach generally rises toward neutral (e.g., physiological or pH 7.14). Moreover, morphine diminishes the transfer of fluid and electrolytes into the lumen of the small intestine via direct effects on the submucosal plexus and within the central nervous system. The dissolution of drugs that are more soluble in water at acidic pH, therefore, may be affected by the coadministration of morphine sulfate.
Fluoroquinolones are zwitterionic compounds in nature, which is due to the presence of both a carboxylic acid and a basic amine group. At low pH, these groups are fully protonated and these compounds carry a net positive charge. Conversely, at high pH the amine is free in the base form and the carboxyl group exists as a carboxylate anion, which results in a net negative charge. For this reason, these compounds tend to be more soluble at acidic and basic pH and less at physiological.
The bioavailability of trovafloxacin mesylate and ciprofloxacin is significantly affected when coadministered with opioids. The AUC of trovafloxacin and ciprofloxacin is decreased approximately 50% when administered concomitantly with these agents.[48,49] Currently, no data exist describing similarly clinically relevant interactions with other advanced generation fluoroquinolones. Moreover, it is possible that more soluble fluoroquinolones, such as gatifloxacin, may not exhibit a similar limitation; however, further studies are necessary.
Several quinolones (e.g., ciprofloxacin, grepafloxacin, enoxacin) have been shown to reduce the clearance of theophylline by inhibition of the cytochrome P-450 enzyme system. On the other hand, 8-fluoro (sparfloxacin), 8-methyoxy (gatifloxacin and moxifloxacin), and C-7 bicyclic (trovafloxacin) substituted quinolones have been studied and exert no change on theophylline pharmacokinetics. Lack of interaction with the cytochrome P-450 system may also be related to dimethylation of the piperazine group at the C-7; however, this is subject to controversy.[30,50]
Semin Respir Crit Care Med. 2000;21(1) © 2000 Thieme Medical Publishers
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