Effects of enoxacin, ofloxacin and norfloxacin on theophylline disposition in humans

Abstract

The effect of three new fluoroquinolones on theophylline kinetics and the urinary excretion of metabolites was studied in 5 healthy subjects (3 male, 2 female). All subjects received serial, single i.v. infusions of theophylline (aminophylline, 250 mg) over 60 min after 200 mg doses of a quinolone (enoxacin, ofloxacin, norfloxacin) every 8 h for 3 consecutive days, the quinolone being administered up to the day following theophylline administration. Pretreatment with ofloxacin and norfloxacin did not influence theophylline disposition, but theophylline clearance fell from 0.054 to 0.027 l.h-1.kg-1 in the presence of enoxacin, without a change in the apparent volume of distribution. Enoxacin, too, was the sole compound to increase the urinary excretion of theophylline (33.2 vs 43.9 mg, before vs after treatment), and significantly to decrease the excretion of 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMU) in 24-h urine samples (from 19.8 to 7.16 mg, from 28.3 to 10.3 mg and from 68.8 to 49.5 mg, respectively). The effect of the quinolones on hepatic drug metabolizing enzyme activity was investigated in each subject using the ratios of 6-hydroxycortisol to total 17-hydroxycorticosteroids and to free cortisol in 24-h urines as an index of the hepatic P-450-dependent enzyme system. No significant difference in ratio was observed between control and other treatments. It is concluded that the theophylline-enoxacin interaction was largely due to inhibition of a metabolic system other than the common hepatic P-450 system.

Effect of fluconazole on theophylline disposition in humans

“…After treatment with enoxacin, the formation clearances of 3-MX, 1-MU, and 1,3-DMU, calculated from their urinary recoveries, showed significant decreases of 69 %, 59 %, and 38 %, respectively (Table 1). This finding agrees well with that reported by Sano et al [13]; enoxacin lowered the CLT of theophylline by inhibiting formation of the three metabolites, especially 3-MX and 1-MU. In contrast, after treatment with fluconazole, the extent of the reduction in the three formation clearances was only 15 %-18 %.…”

“…Enoxacin, a quinolone antibacterial, potently inhibits the oxidative metabolism of theophylline [12,13]. Therefore, comparing test drugs and enoxacin should be a reasonable method of elucidating their potency in inhibiting cytochrome P-4501A-mediated theophylline metabolism in humans.…”

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

“…By comparing the inhibitions between the quinolones in the in vitro human liver microsomal system, we found that the extent of inhibition can be graded as enoxacin > ciprofloxacin > norfloxacin. Sano et al (18) found that the mean cumulative urine recoveries of 3-MX, 1-MU, and 1,3-DMU in humans were decreased from that of control by 64, 63, and 28%, respectively, after administration of enoxacin. These results correlate well with those from our human liver microsomal system (Table 1).…”

Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease

“…Theophylline and its metabolites in urine collected over a dosing interval were also measured on 5 June (no ipriflavone) and 6 August (during ipriflavone) by HPLC [3]. The recovery ratio of 3-methylxanthine was decreased from 17.9 to 11.5 % and of 1-methyluric acid from 29.1 to 25.5 %.…”