New Synthetic Quinolone Antibacterial Agents and Serum Concentration of Theophylline

New Synthetic Quinolone Antibacterial Agents and Serum Concentration of Theophylline* Yoshihito Niki, M.D.; Rinzo Soejima, M.D., F.C.C.P.; Hiroshi Kawane, M.D., F.C.C.P.; Masaro Sumi, M.D.; and Shigenobu Umeki, M.D.

The effect of pipemidic acid and 6ve new synthetic antibacterial agents-norftoxacin, enoxacin, oftoxacin, ciproftoxacin, and peftoxacin-on the serum level of theophylline was studied in healthy male adult volunteers after concomitant oral administration of these agents with a slow release

preparation of theophylline. The results indicated that enoxacin, cipro8oxacin, and pipemidic acid might decrease the clearance of theophylline in the liver, and the attention should be paid in clinical use when enoxacin or pipemidic acid is coadministered with theophylline.

()raI synthetic quinolone derivatives, which

Schedule of the Study

have

been successively developed following the development of norfloxacin (NFLX),l have a much wider antibacterial spectrum and show better tissue penetration than the same type of conventional antibacterial agents such as pipemidic acid (PPA) or nalidixic acid. It has been reported that these new antibacterial agents exhibit excellent clinical efficacy against respiratory tract infections, especially chronic respiratory infections mainly caused by Gram-negative bacteria. 2 It has also been reported, however, that among them, concomitant use of enoxacin (ENX)3.4 with theophylline, often used as a bronchodilator in patients with COPD, leads to a marked increase in the plasma concentration of theophylline, which causes adverse effects. 5.6 Accordingly, we studied the effects of the following six drugs on the serum concentration oftheophylline in healthy male adult volunteers after concomitant oral administration with a slow release theophylline; PPA, NFLX, ENX, oHoxacin (OFLX), ciproHoxacin (CPFX) and peHoxacin (PFX). MATERIALS AND METHODS

Subjects Five healthy male adult volunteers for each drug entered this study. The total number of 30 volunteers were aged 24 to 35 years (mean 29.0 years) with mean height and weight of 171.1 em and 65.8 kg, respectively. One half of the volunteers were smokers. Of the drugs used, ENX and OFLX, and PPA and PFX were studied by using the same volunteers. Before starting this study, all volunteers were confirmed to be normal by physical and laboratory examination; informed consent was obtained.

*From the Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki City, Japan. Manuscript received October 20; revision accepted February 13. Reprint requests: Dr. Niki, Division of Respiratory Diseases, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama, Japan 701-01

The dose levels and administration schedule of the synthetic drugs used were the same as those commonly used for respiratory tract infections in Japan. Namely, PFX was given at 200 mg bid; NFLX, ENX, OFLX, and CPFX at 200 mg tid; and PPA, 500 mg tid, the common dose for urinary tract infections. Theophylline was given as a 100 mg slow release preparation (Theodur) at 200 mg bid. Theophylline and PFX were given at 9:00 AM and 9:00 PM, and other drugs were given one hour after each meal, ie, 9:00 AM, 1:00 PM, and 9:00 PM. Administration and blood sampling schedules are shown in Figure 1. In advance, theophylline alone was given for four days of dosing "around-the-clock" every 12hours to create the same pattern of daily change in the serum theophylline concentration, and then the serum samples were obtained as a control. On the fifth day, concomitant administration of each synthetic antibacterial agent was started. Blood was withdrawn on third and fifth day of the concomitant administration, and serum concentration was compared with that of the control sample (as for PPA, comparison of the value was made on the fifth day only). The blood was obtained immediately before dosing in the morning, ie, zero hour, and then one, two, three, four, six, eight, and ten hours after administration. As to ENX, CPFX, and PFX, the administration of theophylline alone was continued in some volunteers to study changes in the serum theophylline concentration after stopping concomitant administration. In this case, blood samples were obtained twice a day, ie, at zero hour and between four and six hours after dosing. To minimize the variation of drug absorption among volunteers, Day Administration Theophylline Ouinolones

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FIGURE 1. Schedule of administration and sampling. Dose of pipemidic acid is 500 mg tid. CHEST I 92 I 4 I OCTOBER, 1987

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(hr)

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FIGURE 2. Serum concentration of theophylline administered concomitantly with pipemidic acid or pefloxacin. Statistical analysis; * p
_.- + Enoxacin (Day 5) _ ••- + Enoxacin (Day 3)

--- + Ofloxacin (Day 5) -••... + Ofloxacin (Day 3) --Control Mean±S.E.

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or o'

Time after administration (hr)

Crnax±S.E. (pg/ml)

Tmax±S.E. (hr)

AUCo-10±S.E. (I' gohr/ml)

9.84±0.87

5.8±1.0

87.08± 9.27

+ Oftoxacin (Day 3)

10.92±0.44

8.4±0.4

96.92± 5. •

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10.78±0.85

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96.24± 9.39

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FIGURE 3. Serum concentration of theophylline administered concomitantly with enoxacin or ofloxacin. Statistical analysis; * p
684

Synthetic Antibacterial Agentsand Theophylline Concentration (NlkI et aJ)

each volunteer took the same breakfast of approximately 500 calories, one hour before administration, but was not allowed to take foods containing xanthine (coffee, tea, chocolate, etc). They were permitted to follow a normal schedule except for limited drinking and prohibition of excessive exercise.

by the administration of theophylline alone (control value) and by concomitant administration with each drug. Pharmacokinetic parameters are also shown. Figure 2 presents the results obtained with PPA and PFX using the same volunteers. The PPA remarkably increased the theophylline concentration when administered concomitantly. The mean concentrations of Cmax and AUCo-lO were significantly elevated (p
Observation Items

Before and after the study, examination of vital signs, peripheral blood tests, and liver and kidney function tests were performed. Any volunteers who revealed abnormal symptoms were subjected to physical examination and electrocardiography. All volunteers were required daily to report any subjective symptoms. Measurement of Drug Concentration

The serum concentration of theophylline was measured by the fluorescent polarizing immunoassay':" at the Special Reference Laboratories Co. in Tokyo. Statistical Analysis

Comparison of the serum theophylline concentration (mean ± SE) was made between the control values and those obtained in five volunteers at the time of concomitant administration. In addition, comparison of the maximum serum concentration of theophylline (Cmax) and the area under the curve from 0 to 10 hours (AUC()'lJ based on the measured values was also made. Statistical analysis was performed by the paired Student's t-test. RESULTS

Figures 2 to 6 show the changes in mean serum level of theophylline with time in five volunteers obtained

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Time after administration (hr) CHEST I 92 / 4 I OC108ER, 1981

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Condition

shows the individual results from five volunteers. In all volunteers except one (case 1), the serum theophylline concentration on day 5 of concomitant dosing was higher than on day 3. The concentrations for cases 4 and 5 were higher than 20 ug/rnl, Two out of four volunteers (cases 3 and 5) complained of nausea, anorexia, palpitation, or dizziness, all of which were

FIGURE 5. Serum concentration of theophylline administered concomitantly with norfloxacin. Statistical analysis; * p
not so severe as to discontinue the study, and these symptoms disappeared the next day with discontinuation of the concomitant administration. Figures 5 and 6 show results with NFLX and CPFX, respectively. The NFLX caused little change in the serum theophylline level, while on day 3 of concomitant administration, CPFX elevated Cmax (2.28 ...,glml)

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SyntheticAntibacterial Agents and TheophytlineConcentration (NIId .t aJ)

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and AUCO_10 (21.89 fJ.g hr/ml) significantly. The magnitude of these increases tended to be lessened on day 5 as with PFX, and no volunteer complained of any side effects. After the discontinuation of concomitant administration, dosing of theophylline alone was continued in some volunteers receiving ENX, CPFX, and PFX to find how long the effect of coadministration would last. Consequently, as shown in Figure 7, on the next day with withdrawal (follow-up 1), the serum concentration of theophylline for volunteers previously receiving ENX remained rather high, but thereafter, rapidly decreased; that for case 3 almost returned to the control value three days later; and that for case 5 also returned, five days later; In volunteers previously receiving either CPFX or PFX, the theophylline level was decreased to the control values one to three days after the discontinuation of concomitant administration (Tables 1 and 2). DISCUSSION

Our present study demonstrated that PPAand ENX remarkably increased the serum concentration of the-

ophylline to cause side effects when concomitantly used with a slow release theophylline. In addition, CPFX and PFX also elevated the concentration slightly, but to a lesser degree than that with PPA and ENX, and they did not cause any side effects. The NFLX and OFLX were shown to exhibit little effect on the theophylline level. The effects of EN X, CPFX, and PFX disappeared shortly after discontinuation of concomitant administration. Factors affecting the serum concentration of theophylline, or its metabolism, have been reported to include sex, age, liver function, smoking, complications of infections, and others.v" In interaction with concomitantly used drugs, erythromycin,":" and cimetidine":" are well known to increase plasma concentration through inhibition of cytochrome P-450, the main theophylline metabolizing enzyme in the liver." The mechanism of elevation of the serum concentration of theophylline by PPA and ENX is speculated to be attributable to similar enzyme inhibition, and their effect is estimated to be more potent than that of erythromycin. We have already reported on a study using ENX at a dose level of300 mg/day, half the usual dose, in combination with theophylline, 400 mg." in which a slight increase in the plasma theophylline concentration without any side effects was shown. This fact suggests that the effect of ENX is dose dependent. In the present study, the serum level of theophylline on day 5 of concomitant administration of ENX was higher than that on day 3, while in a study using seven-day concomitant dosing;" the theophylline concentration was constant on day 3 or 5 onwards. However; the concomitant use of a slow release theophylline, 400 mg, and ENX, 600 mg (daily dose, respectively), is a standard regimen for COPD and lower respiratory tract infections in [apan.P" Such concomitant use may cause a high incidence of side effects, and this will be a problem in clinical use.

Table I-Serum Concentration ofTheophyUine After Concomitant AdminiBtration ofPeflomcin (PFX) TIme After Administration, hr

o Pefloxacin: Case 3 Control With PFX-day 5 Without PFX-day 3 Without PFX-day 5 Pefloxacin: Case 4 Control With PFX-day 5 Without PFX-day 3 Without PFX-day 5 Pe8oxacin: Case 5 Control With PFX-day 5 Without PFX-day 3 Without PFX-day 5

2

3

4

6

8

10

5.40 9.40 7.20 6.10

6.60 11.40

8.60 11.30

9.80 11.40

9.70 11.00 10.60 10.20

8.80 11.70

7.50 10.20

6.20 9.90

3.90 6.00 4.30 4.20

3.90 6.10

4.20 6.20

4.80 6.80

5.50 7.20 5.30 4.90

5.90 7.40

5.30 7.20

4.20 7.10

7.10 6.80 6.80 5.70

9.20 7.20

9.10 7.80

9.90 8.00

10.30 9.30 9.00 8.30

9.20 9.00

8.20 8.30

7.20 7.80

CHEST I 92 I 4 10000BER, 1987

887

Table 2-Serom Concentration ofTheophyUine After Concomitant Administration ofCiproflomcin (CPFX) TIme After Administration, hr

o Ciprofloxacin: Case 1 Control With CPFX-day 5 Without CPFX-day Without CPFX-day Ciprofloxacin: Case 2 Control With CPFX-day 5 Without CPFX-day Without CPFX-day Ciprofloxacin: Case 3 Control With CPFX-day 5 Without CPFX-day Without CPFX-day

2

3

4

6

8

10

11.50 13.20

10.70 13.20

10.70 13.00

7.60 10.40

7.70 10.40

6.60 8.90

7.00 8.60

6.40 9.30

5.50 8.40

1 2

9.60 11.00 9.60 9.90

9.90 11.10

10.40 12.60

10.60 12.40 9.60 9.60

10.50 12.10

6.10 8.00

5.80

1 2

6.40 8.50 7.10 5.80

9.00

6.40 8.80 6.50 6.50

7.30 9.40

5.30

5.70 8.30

5.60 8.60

5.70 8.00 7.10 5.40

6.10 8.10

1 2

7.50 6.50 5.30

8.90* 10.50*

5.50* 6.70*

7.70* 5.10*

*Five hours.

I J) spite of the fact that the drugs used in this study belong to the same quinolone derivatives group, their effects on the theophylline level vary greatly. However, we have no results that will explain these differences, nor are there any earlier reports that can explain them. Nevertheless, as shown in Figure 8, it has been found that among the drugs used in this study, PPA and ENX considerably increased the serum theophylline concentration and have nitrogen on both 1 and 8 positions, which is the indication of naphthyridine moiety or pvridopyrimidine moiety, while the others have quinoline moiety, To determine whether this fact indicates a structure-effect relationship requires more detailed studies in the future. In any case, the findings of this study should be considered in clinical use and in developing synthetic antibacterial agents having two nitrogen at the 1 and 8 positions with naphthyridine o

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moiety. In summary, NFLX, OFLX, PFX, and CPFXcan be administered concomitantly with slow release theophylline at a standard regimen for respiratory or urinary tract infections. A dose reduction of theophylline, guided by serum concentration monitoring, should be required when coadministered with ENX or PPA. REFERENCES Soejima R, Niki Y, Kawanishi M, Matsushima 1: Tano Y, Katoh 0, et aI. Basic and clinical studies on AM-715. Chemotherapy (Tokyo) 1981; 29(suppl 4):335-42 2 Niki Y, Hino J, Matsushima 1: Kawane H, Nakahama C, Watanabe M, et al. Experimental and clinical studies on the effect of ofloxacin against respiratory tract infections. In Mitsuhashi 5, Daikos GK, eds. OfIoxacin:a new quinolone antibacterial agent: proceedings of a workshop held at the 14th Interna-

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FIG URE 8. Chemical structure of quinolone antibacterial agents.

SyntheticAntibacterial Agentsand Theophylline Concentration (NlkJ st aJ)

3

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tionaI congress of chemotherapy, Kyoto, 1985. Tokyo: University of Tokyo Press, 1986:57-63 Niki Y, Hino J, Watanabe M, Nakahama C, Kawanishi M, Matsushima l: et aI. Bacteriological and clinical studies on AT-2266. Chemotherapy (Tokyo) 1984; 32(suppl 3):554-61 Symposium on new drugs 3 AT-2266, the 31st General Meeting of the Japan Society of Chemotherapy. Osaka, 1983 Wijnanda W}A, Van Herwaarden CLA, Vree TB. Enoxacin raises plasma theophylline concentrations. Lancet 1984; 2:108-09 Maeson FP~ Teengs J~ Baur C, Davis BI. Quinolones and raised plasma concentrations of theophylline. Lancet 1984; 2:530 Jolley ME, Stroupe SD, Wang CHJ, Panas HK, Keegan CD, Schmidt RL, et aI. Fluorescence polarization immunoassay: I. Monitoring aminoglycoside antibiotics in serum and plasma. Clin Chern 1981; 27:1190-97 Hill HD, Jolley ME, Wang CHJ, Quille CL, Keegan DD, Nystrom DL, et aI. Fluorescence polarization immunoassay (FPIA) for theophylline; clinical correlation and reagent stability. Clin Chern 1981; 27:1086 Bukowskyj M, Nakatsu K, Munt PW Theophylline reassessed. Ann Intern Med 1984; 101:63-73 Jonkman JHG, Upton RA. Pharmacokinetic drug interactions

with theophylline. Clin Pharm 1984; 9:309-34 11 Weinberger MM. The theophylline-erythromycin interaction. Chest 1983; 84:310-11 12 Reisz G, Pingleton SK, Melethil 5, Ryan PB. The effect of erythromycin on theophylline pharmacokinetics in chronic bronchitis. Am Rev Respir Dis 1983; 127:581-84 13 Zarowitz BJM, Szefler SJ, Lasezkay GM. Effect of erythromycin base on theophylline kinetics. Clin Pharmcol Ther 1981; 29: 601-05 14 Weinberger MM, Smith G, Milavetz G, Hendeles L. Decreased theophylline clearance due to cimetidine. N Engl J Med 1981; 304:672 15 Rendic 5, Sunijic ~ Toso R, Rfajfez F: Interaction of cimetidine with liver microsomes. Xenobiotica 1979; 9:554-64 16 Danan G, Descatoire V, Pessayre D. Self-induction by erythromycin of it's transformation into a metabolite forming an inactive complex with reduced cytochrome P-450. J Pharmcol Exp Ther 1981; 218:509-14 17 Niki Y, Kawane H, Kishimoto l: Soejima R. Effect of enoxacin on plasma concentration of slow release theophylline. Respir Res, in press

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