Metabolic interactions of ciprofloxacin

DIAG. MICROBIOL.INFECT.DIS. 1990;13:135-141

135

Metabolic Interactions of Ciprofloxacin I

Endre Ludwig, Hedvig Graber, Eva Sz6kely, and Andr is Csiba

The mechanism and clinical relevance of the inhibitory effect of ciprofloxacin on the metabolism of selected drugs were studied in patients with bacterial infections. In study A, antipyrine tests were carried out in two groups of patients taking 1000 mg (group 1) and 250 mg (group 2) of oral ciprofloxacin for 7-10 days. Antipyrine was given intravenously in a dose of 15 mg/kg body weight before and after ciprofloxacin treatment. Blood samples were taken at O, 2, 4, 6, and 10 hr after dosing. In group 1, ciprofloxacin administration resulted in a significant decrease in antipyrine elimination (tl12, 9.45 +- 3.74 vs. 14.92 +_ 3.32 hr). The average decrease in antipyrine clearance was 35% (0.85 +- 0.45 vs. 0.52 + 0.24 ml/min/kg). In group 2, the change in antipyrine kinetics was less pronounced (tl/2, 9.79 +_ 3.06 vs. 11.22 + 2.64 hr). Antipyrine clearance was decreased by only 10% (0.77 +_ 0.13 vs. 0.70 +_ 0.14 ml/min/kg). These results support the hypothesis that ciprofloxacin inhibits the oxidative metabolism in the liver. However, according to the analysis of variance data, the inhibitory effect is dose dependent. At a dose of 1000 mg daily, ciprofloxacin may induce drug interactions whereas, at a dose of 250 mg daily, the likelihood of drug interactions is

improbable. In study B, cimetidine (1000 mg orally daily) and ciprofloxacin (500 mg twice daily) were administered simultaneously to eight patients. Blood samples for the determination of ciprofloxacin concentrations were taken at O, 1, 2, 4, 6, and 12 hr after dosing on the first and seventh day of drug administration. Cimetidine did not significantly influence the elimination of ciprofloxacin (clearance, 11.17 +_ 2.67 vs. 8.67 +_ 4.00 ml/min/kg). In study C, metronidazole (1500 mg oral daily) and ciprofloxacin (500 mg twice daily) were administered simultaneously to eight patients with bacterial infections. Serum concentrations of ciprofloxacin and metronidazole were determined at O, 1, 2, 4, 6, and 12 hr after the first and last dose (7-11 days of therapy). No significant change in ciprofloxacin pharmacokinetics was observed (clearance, 7.0 +_ 3.33 vs. 4.83 +_ 1.83 ml/min/kg). The decline of metronidazole serum concentrations was slower after the last dose than after the first; however, the decrease did not reach statistical significance level (clearance, 1.67 +- 0.50 vs. 1.17 + 0.33 ml/min/kg) and presumably does not have any clinical relevance.

INTRODUCTION

clinical point of view, the inhibition of theophylline metabolism can be regarded as the most important one: ciprofloxacin in a dose of 500-1500 mg orally decreases theophylline clearance by 15-33%; this interaction may result in toxic side effects (Wijnands et al., 1986; Niki et al., 1987; Nix et al., 1987; Raoof et al., 1987; Schwartz et al., 1988). Ciprofloxacin also inhibits caffeine metabolism by presumably the same widely accepted mechanism, i.e., the drug interaction occurs due to the inhibition of hepatic oxidative metabolic processes. Although the exact site of the inhibition has not yet been identified, the quinolones probably inhibit the activity of the cytochrome P-450 enzyme system (Rubinstein and Seger, 1987; Edwards et al., 1988; Harder et al., 1988). We conducted a series of studies to evaluate the clinical relevance of the inhibitory effect of ciprofloxacin. Three questions have been investigated: (1)

Since the first report published by Wijnands et al. in 1984, the interactions of new quinolones have become the focus of much interest. A number of investigations with fluoroquinolones have demonstrated that enoxacin and, to a lesser extent, ciprofloxacin and pefloxacin, decrease the rate of metabolism of some drugs (Edwards et al., 1988). From a From the Department of Medicine and ClinicalPharmacology, P6terfyTeachingHospital, Budapest, Hungary. Address reprint requests to: Dr. E. Ludwig, Department of Medicine and ClinicalPharmacology,P6terfyTeachingHospital, Budapest, VII, POB 76, H-1441, Hungary. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science PublishingCo., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50

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Is the inhibitory effect of ciprofloxacin dose-dependent or not? (2) What is the effect of cimetidine, one of the most potent hepatic cytochrome P-450 system inhibitors, on the kinetics of ciprofloxacin? (3) Do ciprofloxacin and metronidazole each influence elimination of the other? We previously published some parts of this work (Ludwig et al., 1988a and b). This article summarizes our results.

PATIENTS AND METHODS All enrolled patients had bacterial infections and were being treated at either the medical ward or outpatient clinic of our hospital. The study protocols were approved by the ethical committee of the hospital. All patients gave written informed consent prior to participation in the studies.

Study A: Ciprofloxacin-Antipyrine A total of 30 patients were enrolled in the study A. Patients taking other drugs that might have influenced the activity of the microsomal enzyme system were excluded from the study. The ages of the patients ranged from 25 to 82 years. Other characteristics are listed in Table 1. Each patient received two different dosage regimens: 500 mg twice daily (group 1) and 125 mg twice daily (group 2), respectively. The duration of oral ciprofloxacin treatment was 7-11 days. The antipyrine test was carried out before and after ciprofloxacin treatment. Patients were given 15 mg of antipyrine per kilogram of body weight intravenously; blood samples were taken at 0, 2, 4, 6, and 10 hr. The antipyrine serum concentration was

determined by a spectrophotometric method and by high-performance liquid chromatography (HPLC) (Brodie et al., 1949; Weber et al., 1984).

Kinetic Calculations and Statistical Analysis The elimination rate constants (kd) were calculated by linear least square regression analysis of the elimination part of the curve after semilogarithmic transformation. Half-life of antipyrine was calculated from the kel value (tl/2 = 0,693/kel). The area under the curve (AUC) was determined by the trapezoidal rule from the curve up to 10 hr, and then it was extrapolated to infinity by dividing the last concentration value by kel. Total clearance was calculated from the ratio of antipyrine dose to AUC. The 60 value (30 subjects were given two doses of ciprofloxacin) for each parameter (half-life, clearance) were analyzed by two factors (one grouping factor ]dose] and one trial factor [treatment]) ANOVA, with repeated measures for doses, treatments, interaction between these factors, and residual. The significance levels (probability values for different factors) are listed in Table 2.

Study B: Ciprofloxacin-Cimetidine A total of eight patients were enrolled in study B. All suffered from duodenal ulcer and some bacterial infections (Table 1). Cimetidine was administered orally (250 rag, four times a day), whereas ciprofloxacin was administered in a dose of 500 mg twice daily. The duration of ciprofloxacin treatment was 7 days. In addition, all patients were given calciumcontaining antacids and papaverine or meprobamate, if needed. On the first and seventh day of

TABLE 1. Patient Characteristics Study A

Diagnoses

Age (years) Body weight (kg) Serum creatinine (~mol/L)

Group 1 (n = 15)

Group 2 (n = 15)

URTI (2) LRTI (3) UTI (7) BTI (2) PID (1) 57.4 (25-82) 68.6 (42-90) 113 (60-220)

Uncomplicated UTI (15)

56.3 (28-85) 71.2 (55-82) 82 (67-110)

B

C

(n = 8)

(n = 8)

Duodenal ulcer plus bacterial infection (8) 36.2 (28-50) 71.5 (53-87) 86 (65-101)

BTI (5) Gangraena pedis (3) 61.3 (39-76) 72.7 (52-87) 101 (70-145)

URTI, upper respiratory tract infection; LRTI,lower respiratory tract infection; UTI, urinary tract infection; BTI, biliary tract infection; and PID, pelvic inflammatory disease.

Metabolic Interactions

137

TABLE 2. Study A: Analysis of Variance for Antipyrine Kinetics Before and After Treatment Dependent Variable Clearance Source Subject Effect Effect treatment Error

df

Mean Square

p

1 0.0487 NS 1 0.5900 0.001 1 0.2319 0.01 28 0.1954

In group 2 (250 mg ciprofloxacin daily), the change in antipyrine kinetics was less pronounced. Antipyrine clearance decreased 10.2% from 0.77 + 0.26 to 0.70 + 0.27 ml/min/kg, and the average half-life increased from 9.79 + 3.06 to 11.22 + 2.64 hr.

Half-life

df

Mean Square

Study B p

1 41.6667 NS 1 178.1927 0.001 1 61.6107 0.001 28

2.7788

NS, not significant. therapy, blood samples were obtained at 0 (predose), 1, 2, 4, 6, 8, and 12 hr after ciprofloxacin dosing. Serum was assayed for ciprofloxacin by HPLC (Schonfeld et al., 1986).

Study C: Ciprofloxacin-Metronidazole Eight patients suffering from severe bacterial infections were enrolled in study C. Their characteristics, together with the diagnoses, are summarized in Table 1. Ciprofloxacin was administered in a dose of 500 mg twice daily, and metronidazole was administered in a dose of 500 mg twice daily (except for the second dose, which was administered after 12 hr) for 7-10 days. Blood samples were obtained at 0 (predose), 1, 2, 6, and 12 hr after the first and last dose of therapy. The serum concentrations of both drugs were measured by HPLC (Lanbeck and Lindstrom, 1979; Schonfeld et al., 1986).

Kinetic Calculations and Statistical Analysis The pharmacokinetic parameters (/ca, kel, and Vd .... ) were estimated by nonlinear least-square analysis, assuming one compartment open pharmacokinetic model applied. Differences were assessed with Student's t-test. RESULTS

Study A The results of study A are summarized in Figure 1 and Tables 2 and 3. In group 1, ciprofloxacin (1000 mg daily) significantly inhibited the metabolism of antipyrine. Antipyrine clearance decreased 35% (from 0.85 _+ 0.45 to 0.52 _+ 0.24 ml/min/kg), and the average half-life of the test drug increased from 9.45 ___ 3.74 to 14.92 +_ 3.32 hr.

Cimetidine did not significantly influence the kinetics of ciprofloxacin (Fig. 2 and Table 4). Both ciprofloxacin half-life (4.12 ___ 1.02 vs. 4.02 + 1.35 hr) and total clearance of the drug (11.17 ___2.67 vs. 8.67 _ 4.00 ml/min/kg) remained unchanged during the 7-day coadministration with cimetidine.

Study C During the simultaneous administration of ciprofloxacin and metronidazole, slight but insignificant changes were demonstrated in the declines of serum level curves (Figs. 3 and 4, and Table 5). Ciprofloxacin half-life and total clearance did not change significantly (tl/2, 4.55 _+ 2.5 vs. 5.3 --- 2.5 hr; clearance, 7.00 ___3.33 vs. 4.83 + 1.83 ml/min/kg). A slight tendency of decrease in total clearance was found, but we presume it corresponds to the expected tendency in this age group (average, 61.3 years) of patients treated with monotherapy. Like the changes in ciprofloxacin kinetics, a tendency of decreased elimination was demonstrated in metronidazole kinetics as well, but it did not reach the statistically significant level (tl/2, 6.97 ___ 3.46 vs. 8.11 _ 3.74 hr; clearance, 1.67 + 0.50 vs. 1.17 + 0.33 ml/min/kg).

DISCUSSION During recent years, interest in the metabolic interactions of new quinolones has increased. The reason for this interest is evident: the quinolones represent a group of antimicrobial agents with powerful activity against the majority of h u m a n pathogens; because of their safety and tolerability, a great number of patients can be treated with them both in hospital wards and outpatient clinics. Because more and more patients are going to receive quinolones and the majority of them take other drugs simultaneously, learning the interactions and their clinical relevance is of the utmost importance.

Ciprofloxacin-Antipyrine In our studies we first aimed at gathering further information on the inhibitory effect of ciprofloxacin: does it influence the kinetics of antipyrine, or does the rate of inhibition depend on the dose of ciprofloxacin? We investigated these questions with the

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before treatment

50-

after treatment

30r

20i

L

r

r

10-

i

t

Group 1 ....

FIGURE 1.

T A B L E 3.

Group 2

Antipyrine serum concentrations before and after ciprofloxacin treatments.

S t u d y A: K i n e t i c P a r a m e t e r s of A n t i p y r i n e Before a n d A f t e r C i p r o f l o x a c i n T r e a t m e n t ( m e a n _+ SD) Group 1 Treatment

tl/2 (hr) V (L/kg) Clearance (ml/min/kg) AUC a (mg.hr/L)

Group 2 Treatment

Before

After

Before

After

9.45 ± 3.74 0.58 ± 0.11 0.85 ± 0.45

14.92 ± 3.32 0.61 _+ 0.13 0.52 _+ 0.24

9.79 ± 2.06 0.58 4- 0.07 0.77 +_ 0.13

11.22 ± 2.60 0.59 ± 0.08 0.79 ± 0.14

337.2 ± 144.0

522.8 ± 180.1

352.1 ± 117.1

411.9 ± 181.7

"0-~ before treatment and after treatment.

(mo/I)

7th day

1st day

432-

1-

0.5-

0.2-

i

iII

i

i i i

FIGURE 2. Ciprofloxacin serum concentrations on the first a n d seventh day of simultaneous administration of ciprofloxacin and cimetidine.

Metabolic Interactions

TABLE 4.

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Study B: Pharmacokinetic Parameters of Ciprofloxacin Given Simultaneously with Cimetidine (mean + SD)

Cmax (t~g/ml) tl/2 (hr) Total clearance (ml/min/kg) V (L/kg) AUCb (mg.hr/L)

Day 1

Day 7

1.49 +- 0.37 4.16 -+ 1.59 11.17 -+ 2.67

3.08 -+ 0.36 4.02 + 1.35a 8.67 + 4.00a

3.74 + 1.42 11.22 + 3.36

3.08 -+ 1.94a 15.16 - 5.7¥

intensively studied hepatic enzyme inhibitors. In an in vitro study, Hoensch et al. (1985) demonstrated that the extent of inhibition of O-dealkylation and of 7-ethoxycoumarin depends on the concentration of cimetidine. In 1987, Somogyi and Muirhead reviewed reports that found the inhibitory effect of cimetidine to be dose dependent in humans. The first observations on the dose-dependent inhibitory effect of quinolones on metylxanthine derivatives were provided by Harder et al., (1988). They found that the extent of inhibition of caffeine and theophyUine by the studied quinolone derivatives was dosedependent. Ciprofloxacin at 100 mg twice daily resulted in only a slight increase in the half-life of paraxanthine but had a small but significant effect on the elimination of caffeine and paraxanthine in excess of 250 mg twice daily. Ciprofloxacin at 1000 mg daily decreased the elimination of caffeine 1.3fold. Rogge et al. (1988) have also recently demonstrated that enoxacin exhibits a dose-dependent inhibitory effect: enoxacin given for 7 days in a dose of 25, 100, or 400 mg twice daily increased the halflife of theophylline from the 7.78 hr of the control to 10.5, 13.5, and 14.2 hr, respectively. A review of the literature reveals that there are no other published studies to date that report on the dose-dependent inhibitory effect of ciprofloxacin in humans. From the survey of studies dealing with theophylline--ciprofloxacin interactions, we could not find any correlation between the dosage of ciprofloxacin and the decrease in theophylline clearance: in the range of 500-1500 mg daily, theophylline clearance was decreased by 17-33% independent of the administered dose. Nevertheless, one has to take

ap > 0.05. bo--o~on day 1 and 0-12 on day 7. help of the antipyrine test, and some parts of the results have already been published (Ludwig et al., 1988a, 1988b). We demonstrated that oral ciprofloxacin in a dose of 500 mg twice daily significantly decreases the total clearance of antipyrine. Because the elimination of antipyrine depends only on the intrinsic metabolic capacity of the liver, this provides indirect but convincing evidence of the inhibition of the monoxidative enzyme system by ciprofloxacin. Other data that have been accumulated in the literature on the inhibitory effect of quinolones have recently been reviewed by Edwards et al. (1988). Whereas ciprofloxacin in a daily dose of 1000 mg decreased the antipyrine clearance by 35%, 250 mg daily resulted in only a 10% decrease. This suggests that the extent of inhibition is dose-dependent. However, there are only a few published studies on the dose dependency of drug metabolism. In recent years, cimetidine was one of the most C

rmg/,It ~1

1stday

lastday

2

i ~. I

I

FIGURE 3. Ciprofloxacin serum concentrations on the first and last day of simultaneous administration of ciprofloxacin and metronidazole.

140

E. L u d w i g et al.

C

(rag/')l

lo

last day

1st day

1

5-

2-

I

I ~r]

6

12

;ih)

FIGURE 4. Metronidazole serum concentrations on the first and last day of simultaneous administration of ciprofloxacin and metronidazole. into consideration the subjects of these studies (Wijnands et al., 1986; Niki et al., 1987; Nix et al., 1987; Raoof et al., 1987) c o m p r i s e d healthy y o u n g v o l u n t e e r s and severely ill patients, and their ages also r a n g e d within b r o a d limits. Therefore, t h e y cannot be r e g a r d e d as comparable g r o u p s . W h a t kind of conclusions can be d r a w n from these results, and w h a t kind of n e w problems have to be a n s w e r e d in the future? It seems v e r y probable that the inhibitory effect of q u i n o l o n e s is dose d e p e n d e n t . Presumably, the rate of inhibition reaches clinical relevance only in a dose of > 250 mg, a n d clinically significant d r u g interactions are to be expected w h e n administering ciprofloxacin in a dose of 500-1500 mg. It m u s t also be investigated w h e t h e r the extent of inhibition dep e n d s o n the s e r u m concentration profile and dose of ciprofloxacin or on the route of administration; i.e., the same inhibitory effect should d e v e l o p after the administration of 500 m g orally or 200 m g intravenously. Obviously, if one suggests that the inhibitory effect of ciprofloxacin d e p e n d s on its concentration w h e n entering the liver, the question can be

TABLE 5.

a n s w e r e d , at least in principle. P r e s u m i n g the absorption half-life is 1/4 hr a n d the blood flow t h r o u g h the portal vein is 72 L/hr the expected ciprofloxacin concentration after 500 m g orally is - 4.5 }xg/ml in portal blood in the e v e n t of 80% bioavailability. This is about three times h i g h e r t h a n the expected v e n o u s concentration after 200 m g intravenously. O n the basis of this, it seems probable that after i n t r a v e n o u s administration, the inhibitory effect of ciprofloxacin is less t h a n that after oral administration.

Ciprofloxacin-Cimetidine Cimetidine has p r o v e d to be one of the most p o t e n t e n z y m e inhibitors (Somogyi and Muirhead, 1987), because of its w i d e s p r e a d use, its frequent coadministration with ciprofloxacin is to be expected. According to H o f f k e n et al. (1986), cimetidine did not inhibit the metabolism of ciprofloxacin. H o w e v e r , the total clearance of pefloxacin was inhibited 30% by cimetidine (Soergel et al., 1986); this observation left some uncertainty concerning the interaction of

S t u d y C: Pharmacokinetic Parameters of Ciprofloxacin and Metronidazole Given Simultaneously (mean + SD) Ciprofloxacin

Cmax(Ixg/ml) t~z2(hr) Total clearance (ml/min/kg) V (L/kg) AUC c (mg. h/L)

Metronidazole

Day 1

Day 7

Day 1

Day 7

2.04 ± 0.56 4.55 ± 2.50 7.00 _+ 4.33

2.96 ± 0.89 5.30 ± 2.50" 4.83 ± 1.83"

6.25 ± 1.38 6.97 _+ 3.46 1.67 ± 0.50

12.32 ± 5.10 8.11 ± 3.74" 1.17 ± 0.33~

2.16 ± 0.56 21.10 ± 13.29

2.34 ± 0.37" 25.20 ± 6.59a

0.91 ± 0.37 75.18 ± 33.69

0.81 ± 0.31" 121.11 ± 46.44 b

"p > 0.05. ~'p < 0.05. '0-~ on day 1 and 0-12 hr on the last day.

Metabolic Interactions

quinolones and H2 antagonists (Rubinstein and Seger, 1987). In our study, 1000 mg cimefidine daily did not significantly inhibit the metabolism of ciprofloxacin; therefore, our data confirmed the conclusions of the above-mentioned investigators. Considering the possible dose dependency of inhibition, the inhibitory effect of cimetidine in a dose in excess of 1000 mg cannot be ruled out.

Ciprofloxacin-Metronidazole The combination of ciprofloxacin-metronidazole is frequently used in the treatment of mixed infections. Boeckh et al. (1988) recently published a report that metronidazole did not alter the kinetics of ciprofloxacin. In our study, decreased elimination in the case

141

of both drugs could be detected, but neither of them reached the statistically significant level. Our patients suffered from severe infections and they were mostly over 60 years of age, so the role of age-associated changes or other factors in the change of ciprofloxacin kinetics has to be taken into consideration. The tendency of decrease in metronidazole elimination raises the possibility of drug interactions, but further studies are needed to answer this question. Nevertheless, this interaction--if it does exist--presumably does not bear any clinical significance. The inhibition of antipyrine metabolism by ciprofloxacin is dose-dependent. Coadministration of ciprofloxacin with cimetidine or metronidazole does not result in clinically significant drug interactions.

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Nix DE, De Vito JM, Whitbread MA, Schentag JJ (1987) Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanin green. J Antimicrob Chemother 19:263-269. Raoof S, Wollschlager C, Khan FA (1987) Ciprofloxacin increases serum levels of theophylline. Am ]Med 82(suppl 4A):115-118. Rogge MC, Solomon WR, Sedman AJ, Welling PG, Toothaker RD, Wagner JG (1988) The theophyllineenoxacin interaction. I. Effect of enoxacin dose size on theophylline disposition. Clin Pharmacol Ther 44:579-587. Rubinstein E, Seveg S (1987) Drug interaction of ciprofloxacin with other non-antibiotic agents. Am J Med 82(suppl 4A):119-123. Schonfeld W, Knoller J, Bremm KD, Dahlhoff A, Weber B, Konig W (1986) determination of ciprofloxacin, norfloxacin and ofloxacin by high performance liquid chromatography. Zentralbl Bakteriol Parasitenkole Infektionskr Hyg Abt Orig Reihe A 261:338-344. Schwartz J, Jaurequi L, Lettieri J, Bachmann K (1988) Impact of ciprofloxacinon theophylline dearance and steady state concentrations in serum. Antimicrob Agents Chemother 32:75-77. Soergel F, Koch U, Metz R, Stephan V (1986) Cimefidine inhibits the hepatic metabolism of pefloxacin (abstr 390). In Proceedings of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, Louisiana. Somogyi A, Muirhead M (1987) Pharmacokinetic interactions of cimetidine. Clin Pharmacol 12:321-366. Weber A, Opheim K, Smith AL (1984) Simplified high performance liquid chromatographic quantitation of antipyrine. J Chromatogr Sci 22:239-240. Wijnands WJA, Van Herwaarden CLA, Vree TB (1984) Enoxacin raises plasma theophylline concentrations. Lancet 2:108-109. Wijnands WJA, Vree Tb, Van Herwaarden CLA (1986) The influence of quinolone derivatives on theophylline clearance. J Clin Pharmacol 22:677-683.