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HSR-903 is a newly developed quinolone which has broader and more potent activities against both gram-positive and gram-negative bacteria (7) and chlamydiae (5) than conventional quinolones under clinical evaluation in Japan. It has been reported that some quinolones, such as enoxacin, lead to a marked increase in the concentration of theophylline in serum when they are coadministered with theophylline, resulting in an increased risk of serious side effects (2, 8). It is, therefore, clinically important to evaluate whether a quinolone increases the theophylline concentrations in serum when it is administered concomitantly. Accordingly, we studied the effect of HSR-903 on the concentrations of theophylline in serum in healthy male adult volunteers.

Six healthy adult male volunteers (age, 25.3 ± 5.7 years; mean ± standard deviation [SD]; body weight, 60.4 ± 5.6 kg) participated in this study. Subjects were excluded from the study if they smoked tobacco, used drugs of any kind, or were known to have a drug allergy. Before this study was started, physical and laboratory examinations confirmed that all subjects were healthy. Informed written consent was obtained from all subjects after a full explanation of the objectives and possible risks of the study was given to them. The study protocol was approved by the local Institutional Review Board of Sekino Hospital.

Theophylline tablets in a sustained-release formulation (Theodur; 200 mg of theophylline per tablet; Nikken Kagaku, Tokyo, Japan) were used in this study. Likewise, the tablet form of HSR-903 containing 100 mg of active ingredient (Hokuriku Seiyaku Co., Ltd., Fukui, Japan) was used.

A 200-mg theophylline tablet was administered orally to subjects every 12 h (9 a.m. and 9 p.m.) for 8 days and the morning of day 9 (9 a.m.). The dose was ingested with 180 ml of water 30 min after a meal. HSR-903 was taken orally in 200-mg doses every day in the morning, and theophylline was taken with it on study days 5 through 9. Vital signs were measured daily.

Blood was collected by venipuncture from an antecubital or forearm vein and was placed in evacuated glass tubes. Within 1 h after collection, the tubes were centrifuged for 10 min and the obtained serum samples were frozen at 20°C until assayed. Serum samples were taken at 12 h after the first dosing of every day; at 0, 1, 2, 3, 4, 6, 8, and 10 h after dosing on days 4 (theophylline given alone), 7 (day 3 of concomitant dosing), and 9 (day 5 of concomitant dosing); and at 0 h after dosing on day 6. In this study, theophylline concentrations in serum were measured daily, and it was confirmed before the start of and during treatment with HSR-903 that theophylline levels had reached steady state.

The concentrations of theophylline in serum were determined by fluorescence polarization immunoassay (TDx; Dainabot Co., Ltd., Tokyo, Japan). The quantitative limit for the assay method is 0.82 µg/ml, and the coefficients of variation are 2.23, 1.44, and 1.42% at theophylline concentrations of 7.0, 12.0, and 25.1 µg/ml, respectively.

The concentrations of theophylline and its metabolites in urine were measured by the method of Scott et al. (6) with minor modifications, using high-performance liquid chromatography. A chromatographic separation was achieved with a Nucleosil 7C₁₈ (250- by 4.6-mm inside diameter; 7-µm particle size; GL Sciences) with a gradient elution system; the eluent for pump A was 0.01 M acetate buffer (pH 4.8) containing 0.5% tetrahydrofuran (THF), and for pump B, it consisted of a mixture of 0.01 M acetate buffer (pH 4.8) containing 0.5% THF and acetonitrile (85:15, vol/vol). The linear gradient from pump A to pump B was achieved in 16 min. The flow rate was 1.5 ml/min. The peaks were monitored with UV at 280 nm. The column temperature was maintained at 40°C. The quantitative limit for the assay of urinary theophylline and its metabolites is 5 µg/ml, and the coefficients of variation are 0.35 to 1.02% for theophylline, 0.59 to 3.21% for 1-methyluric acid (1-MU), 0.59 to 1.98% for 3-methylxanthine (3-MX), and 0.45 to 2.68% for 1,3-dimethyluric acid (1,3-DMU) at the concentration range of about 5 to 500 µg/ml.

A model independent estimate of the apparent theophylline total body clearance (CL_TB/F) was calculated for each of the following steady-state periods: before HSR-903 treatment (study day 4) and during HSR-903 treatment (study days 7 and 9, corresponding to days 3 and 5 of concomitant dosing, respectively). CL_TB/F was calculated as D/AUC, where CL_TB is the actual total body clearance of theophylline, F is the fraction of the theophylline dose absorbed systemically, D is the dose of theophylline at each dosing interval (), and AUC is the area under the serum concentration-time curve for a dosing interval. AUC was determined by using the trapezoidal rule.

Theophylline concentrations in serum were analyzed by using repeated measure analysis of variance. Differences were regarded as significant at a P value of <0.05. Differences between the maximum concentrations in plasma (C_max), the times of arrival to the C_max (T_max), AUC, and CL_TB/F on day 4 and day 3 of concomitant dosing and on day 4 and day 5 of concomitant dosing were assessed with the Wilcoxon signed-rank test. Differences were regarded as significant at a P value of <0.025.

The study of the effect of HSR-903 was performed on six healthy male volunteers, but one of the volunteers complained of a severe rash and itching on day 4 of concomitant dosing, so the medication was discontinued. Therefore, the effect of HSR-903 was evaluated in five volunteers only. Side effects were observed in two volunteers, mild epigastric discomfort in one and slight elevation of alanine aminotransferase in the other, but they were transient.

The pharmacokinetic parameters of theophylline (C_max, T_max, AUC, and CL_TB/F) are shown in Table 1. All parameters on days 3 and 5 of concomitant dosing were not significantly different from those on day 4 (control). The C_max on days 3 and 5 of concomitant dosing were 9.6 and 9.7 µg/ml, respectively, compared to that on day 4 (7.9 µg/ml), and the rates of increase were 22 and 23%, respectively. Similarly, the AUC values on days 3 and 5 of concomitant dosing (103.8 and 104.6 µg · h/ml, respectively) were higher than that on day 4 (84.6 µg · h/ml), and the rates of increase were 23 and 24%, respectively. By contrast, CL_TB/F values on days 3 and 5 of concomitant dosing (32.8 and 32.3 ml/min) were lower than that on day 4 (40.3 ml/min), and the rates of decrease were 19 and 20%, respectively.

Urinary excretion rates of theophylline and its metabolites are shown in Table 2. Urinary excretion rates of theophylline on days 3 and 5 of concomitant dosing were higher than that on day 4, though the difference is not significant. On the other hand, the excretion rates of theophylline metabolites 1-MU and 3-MX on days 3 and 5 of concomitant dosing were lower than those on day 4, though the differences are not significant, while the excretion rates of 1,3-DMU were nearly equal among the three periods.

Since some quinolones inhibit the hepatic microsomal enzyme CYP1A2, which catalyzes theophylline metabolism to 1-methylxanthine (1-MX) and which is further metabolized to 1-MU by xanthine oxidase and 3-MX, the concentration of theophylline in serum increases upon concomitant administration of these quinolones. As shown in Table 3, the extent to which quinolones increase the theophylline concentration in serum varies among the quinolones. Enoxacin and pipemidic acid increase the C_max and AUC of theophylline by at least 40% and are classified as class I quinolones (4). Grepafloxacin, prulifloxacin, tosufloxacin, ciprofloxacin, and pefloxacin increase the C_max and AUC of theophylline by 15 to 39% and are classified as class II quinolones (3, 4). Ofloxacin, gatifloxacin, norfloxacin, levofloxacin, sparfloxacin, pazufloxacin, fleroxacin, lomefloxacin, and temafloxacin increase the theophylline concentration in serum by less than 15%, if at all, and are classified as class III quinolones (1, 4).

The urinary excretion of theophylline tended to increase by concomitantly administered HSR-903, while the urinary excretions of 1-MU and 3-MX tended to decrease. These results indicated that because HSR-903 also inhibited the hepatic microsomal enzyme CYP1A2, the concentration of theophylline in serum increased by concomitantly administered HSR-903. Because HSR-903 increases the C_max and AUC of theophylline by 23 and 24%, respectively, it is classified as a class II quinolone.

In conclusion, HSR-903 proved to slightly increase the theophylline concentrations in serum and was classified as a class II quinolone, indicating that the theophylline concentration in serum should be monitored and the theophylline dose should be adjusted if concomitant administration of theophylline and HSR-903 is necessary.