New Synthetic Quinolone Antibacterial Agents and Serum Concentration of Theophylline

Niki, Yoshihito; Soejima, Rinzō; Kawane, Hiroshi; Sumi, Masaru; Umeki, Shigenobu

doi:10.1378/chest.92.4.663

Cited by 57 publications

(25 citation statements)

References 9 publications

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“…Enoxacin is the most potent inhibitor of theophylline metabolism in vivo, followed by ciprofloxacin. Ofloxacin and norfloxacin cause only slight inhibition (12,23). We investigated an in vitro system of human microsomes, the results of which correlate well with that observed for in vivo interactions of quinolones with theophylline.…”

Section: Resultssupporting

confidence: 70%

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

Sarkar

Polk

Guzelian

et al. 1990

Antimicrob Agents Chemother

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Some quinolone antibiotics cause increases in levels of theophylline in plasma that lead to serious adverse effects. We investigated the mechanism of this interaction by developing an in vitro system of human liver microsomes. Theophylline (1,3-dimethylxanthine) was incubated with human liver microsomes in the presence of enoxacin, ciprofloxacin, norfloxacin, or ofloxacin. Theophylline, its demethylated metabolites (3-methylxanthine and 1-methylxanthine), and its hydroxylated metabolite (1,3-dimethyluric acid) were measured by high-pressure liquid chromatography, and Km and Vm,,, values were estimated. Enoxacin and ciprofloxacin selectively blocked the two N demethylations; they significantly inhibited the hydroxylation only at high concentrations. Norfloxacin and ofloxacin caused little or no inhibition of the three metabolites at comparable concentrations. The extent of inhibition was reproducible in five different human livers. Inhibition enzyme kinetics revealed that enoxacin caused competitive and mixed competitive types of inhibition. The oxo metabolite of enoxacin caused little inhibition of theophylline metabolism and was much less potent than the parent compound. Nonspecific inhibition of cytochrome P-450 was ruled out since erythromycin N demethylation (cytochrome P-450 mediated) was unaffected in the presence of enoxacin. These in vitro data correlate with the clinical interaction described for these quinolones and theophylline. We conclude that some quinolones are potent and selective inhibitors of specific isozymes of human cytochrome P-450 that are responsible for theophyiline metabolism. This in vitro system may be useful as a model to screen similar compounds for early identification of potential drug interactions.

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Section: Resultssupporting

confidence: 70%

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

Sarkar

Polk

Guzelian

et al. 1990

Antimicrob Agents Chemother

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“…The in vivo experiments in this study showed that ENX markedly and NFLX slightly prolonged the T1 /2 of theophylline in rats, but OFLX did not affect it. Many investigators have reported a similar result in human sub jects, that ENX markedly raised the plasma theophylline concentration and prolonged its T1 /2, whereas NFLX and OFLX had little or no effect on the pharmacokinetics of theophyl line (1)(2)(3)(4)(5)(6)(7)(8). Sekine et al (12) and Okazaki et al (26) have shown similar results in rats con cerning ENX and OFLX.…”

Section: Discussionmentioning

confidence: 73%

“…(The chemi cal structures of the quinolones discussed in this report are shown in Fig. 12.) Niki et al (8) compared the effects of 6 quinolones on theophylline metabolism. They reported that among the 6 drugs investigated, ENX and pipemidic acid both considerably increased the serum theophylline concentration and both had nitrogen at positions 1 and 8 (naph thyridine or pyridopyrimidine ring), while the other drugs had nitrogen only at position 1 (quinoline ring).…”

Section: Discussionmentioning

confidence: 99%

“…Since then, many investigators have demonstrated that ENX raises the plasma theophylline concentration and prolongs its elimination half-life (T1 /2). In contrast, other new quinolones, such as norfloxacin (NFLX) and ofloxacin (OFLX), have no or only a slight effect on the pharmacokinetics of theophyl line (2)(3)(4)(5)(6)(7)(8). It appears that the increase in the plasma theophylline concentration is due to a reduced metabolic clearance of theophylline in the liver induced by ENX, while NFLX and OFLX seem to have little effect on drug metabolizing activity in the liver.…”

Section: Acceptedmentioning

confidence: 99%

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Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

Nakanishi

Okuno

1990

Japanese Journal of Pharmacology

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Abstract-The effects of three new quinolones (enoxacin (ENX), norfloxacin (NFLX) and ofloxacin (OFLX)) on acetaminophen-induced liver injury in rats were examined and compared with their effects on the elimination half-life (T1/2) of theophylline (in vivo) and on the 7-ethoxycoumarin (7-EC) O-deethylase activity in liver microsomes (in vitro).ENX, NFLX and OFLX (75 or 300 mg/kg) were administered orally to rats 1 hr before, simultaneously with, and 1 hr after the acet aminophen injection (800 mg/kg). Biochemical liver function tests, drug me tabolizing activity in liver microsomes, the total glutathione content of the liver and histological changes were examined 5 hr after the acetaminophen injection. ENX markedly reduced acetaminophen-induced liver injury and NFLX slightly but sig nificantly did so, but no protective effect was observed with OFLX treatment. ENX markedly and NFLX slightly prolonged the T1/2 of theophylline, but OFLX did not affect it. In addition, ENX markedly and NFLX slightly inhibited the 7-EC Odeethylase activity in liver microsomes, but OFLX again had no effect. These findings indicated that ENX markedly inhibited the activity of cytochrome P-450 in liver microsomes and NFLX did so slightly, while OFLX had no such effect. Slight variations in the structures of these quinolones might explain the differences in their effects on cytochrome P-450 activity.In recent years, several new quinolones have been developed as effective antibacterial agents and widely used to treat a variety of infections. In 1984, Wijnands et al. (1) first reported that co-administration of enoxacin (ENX), one of the new quinolones, with theophylline raised the plasma theophylline concentration, and that eight of the ten pa tients who received theophylline in combina tion with ENX developed serious nausea and vomiting. Since then, many investigators have demonstrated that ENX raises the plasma theophylline concentration and prolongs its elimination half-life (T1 /2). In contrast, other new quinolones, such as norfloxacin (NFLX) and ofloxacin (OFLX), have no or only a slight effect on the pharmacokinetics of theophyl line (2-8). It appears that the increase in the plasma theophylline concentration is due to a reduced metabolic clearance of theophylline in the liver induced by ENX, while NFLX and OFLX seem to have little effect on drug metabolizing activity in the liver. However, little in vitro evidence has been reported that the new quinolones affect the activity of drug metabolizing enzymes in liver microsomes.Cimetidine, which is known to inhibit the drug metabolizing activity in liver microsomes (9), has been reported to prevent acetamino phen-induced liver injury (10, 11), but there have been no reports concerning the effects of the new quinolones on acetaminophen induced liver injury.In the present study, the protective effects of three new quinolones (ENX, NFLX and OFLX) on acetaminophen-induced acute liver injury in rats were investigated and com pared with each other. Moreover, the effects of these new quinolone...

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“…Several of the new fluoroquinolones, including ciprofloxacin, have been reported to interfere with the clearance of theophylline, leading to elevated concentrations of theophylline in serum and central nervous system (CNS) toxicity (2,14,16,19,22; F. P. V. Maesen, J. P. Teengs, C. Baur, and B. I. Davies, Letter, Lancet ii:530, 1984). Caffeine, a methylxanthine, is similar in structure to theophylline and is widely consumed in the form of caffeinated beverages.…”

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confidence: 99%

Interaction between oral ciprofloxacin and caffeine in normal volunteers

Healy

Polk

Kanawati

et al. 1989

Antimicrob Agents Chemother

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The influence of multiple doses of ciprofloxacin on the disposition of caffeine and its major metabolite, paraxanthine, was investigated in healthy volunteers. Ten xanthine-free, fasting males were given 100 mg of caffeine orally 24 h before being given ciprofloxacin and again with the third dose of ciprofloxacin (750 mg administered every 12 h). Blood samples were serially collected after both doses of caffeine and after the first and last doses of ciprofloxacin. Ciprofloxacin significantly increased the half-life of caffeine (from 5.2 ± 1.2 to 8.2 ± 2.5 h) and the area under the caffeine concentration-time curve (from 16.3 ± 6.6 to 25.9 + 7.8 ,g * h/ml) while decreasing the total body clearance (from 106 ± 41.6 to 58.2 ± 28.8 ml/min per 1.73 m2). In addition, the rate of conversion of caffeine to paraxanthine was significantly delayed. There was no significant linear correlation between the urinary recovery of oxociprofloxacin at 0 to 12 h and the change in the area under the caffeine concentration-time curve. There was also a small but statistically significant increase in the area under the ciprofloxacin concentration-time curve during simultaneous administration of caffeine. We concluded that ciprofloxacin causes a significant increase in the half-life of caffeine and in the area under the caffeine concentration-time curve by reducing total body clearance. This interaction is due at least in part to a delay in the conversion of caffeine to paraxanthine. The clinical significance of these observations remains to be determined. Lastly, caffeine may alter the kinetics of ciprofloxacin, a possibility which should be more fully explored.

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New Synthetic Quinolone Antibacterial Agents and Serum Concentration of Theophylline

Cited by 57 publications

References 9 publications

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

Interaction between oral ciprofloxacin and caffeine in normal volunteers

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