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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1991, p. 130-134 0066-4804/91/010130-05$02.00/0 Copyright © 1991, American Society for Microbiology

Influence of Subject Age

on

Vol. 35, No. 1

the Inhibition of Oxidative Metabolism

by Ciprofloxacin KRAKOVSKY,1l JOEL D. STEINBERG,3'4 LAWRENCE H. WARBASSE,3'4 AND DAVID J. EDWARDS' 2* College of Pharmacy & Allied Health Professions' and School of Medicine,3 Wayne State University, Detroit, Michigan NANCY M. WAITE,1'2t MICHAEL J. RYBAK,"2 DAVID J.

48202, and Departments of Pharmacy Services2 and Medicine,4 Detroit Receiving Hospital, Detroit, Michigan 48201 Received 9 July 1990/Accepted 5 November 1990

Case reports suggest that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin may be greater in elderly subjects. We examined the effect of oral ciprofloxacin on antipyrine disposition in 13 young (ages, 23 to 34 years) and 9 elderly (ages, 65 to 82 years) healthy volunteers. Ciprofloxacin decreased antipyrine oral clearance in young and elderly subjects (P < 0.05), with the average decreases being similar in both groups (23.3% for the young subjects and 27.9% for the elderly subjects). Ciprofloxacin concentrations in serum were significantly higher (mean, 57%) in the elderly. The formation clearance of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was also significantly decreased in both groups of subjects; however, norantipyrine formation, accounting for 15 to 20% of antipyrine clearance, was reduced only in the elderly. These results suggest that elderly subjects are not more sensitive to the inhibitory effect of ciprofloxacin on antipyrine metabolism. However, careful clinical monitoring is necessary with all patients, irrespective of age, taking ciprofloxacin concomitantly with drugs primarily eliminated by the cytochrome P-450 system.

MATERIALS AND METHODS Subjects. Thirteen young healthy volunteers (six females and seven males) between the ages of 23 and 34 (mean, 26.8 years) and nine elderly healthy volunteers (six females and three males), ranging from 65 to 82 years of age (mean, 71.6 years), participated in the study. Healthiness was confirmed by medical history, physical examination, biochemical profile, and blood count prior to the study. Weights were similar in both groups (average of 69.7 and 72.6 kg for young and elderly, respectively). Subjects were nonsmokers who were not taking any medications known to interfere with drug metabolism and abstained from over-the-counter medications, alcohol, and caffeine for 24 h prior to and throughout the study. A consent form, approved by the Wayne State University Human Investigation Committee, was reviewed and signed by all subjects. Study design. The study was conducted by using a randomized, crossover design with a 1-week washout period between phases. Following an overnight fast, a single oral dose of antipyrine (1 g of antipyrine powder in a gelatin capsule) was administered at 0800 h either alone or on the third day of oral ciprofloxacin (CIPRO [Miles Pharmaceuticals]) treatment (500 mg at 0800 and 2000 h for 4 days). All doses of ciprofloxacin were taken on an empty stomach. Blood samples for antipyrine assay were collected at 8, 24, 32, and 48 h after antipyrine administration. In addition, ciprofloxacin concentration was measured in the sample collected 8 h following coadministration of ciprofloxacin and antipyrine. Urine was collected for 48 h after each dose of antipyrine into containers with 2 g of sodium metabisulfite. Serum and urine samples were stored at -20°C prior to analysis. Assays. Antipyrine concentration in serum was measured in our laboratory, using high-performance liquid chromatography (18). This assay has a sensitivity of 0.1 mg/liter and a coefficient of variation averaging less than 5% over the concentration range encountered in this study. The method of Blyden et al. (1) was used to determine the concentration of antipyrine and its major metabolites in urine. Ciproflox-

Ciprofloxacin is a fluoroquinolone antibiotic with widespread therapeutic application because of its broad spectrum of antibacterial activity, oral effectiveness, and low incidence of serious adverse effects. Studies over the past few years have established that several fluoroquinolones, including ciprofloxacin, inhibit the oxidative hepatic metabolism of a number of substrates (3). Most of these studies have involved young healthy volunteers. However, case reports and a retrospective study suggest that the magnitude of inhibition may be greater in elderly subjects. Raoof et al. (12) evaluated the effect of ciprofloxacin on theophylline concentrations in 33 hospitalized patients and found that the patients who experienced significant increases in theophylline concentrations were older than those.who did not. Case reports by Rybak et al. (15) and Thomson et al. (19) described elderly patients (82 and 92 years of age, respectively) with therapeutic (10 to 15 mg/liter) theophylline concentrations who experienced increases to more than 30 mg/liter after starting therapy with ciprofloxacin. Estimated theophylline clearance decreased by 56 and 64%, respectively, in these reports, substantially greater than the average decrease of 15 to 30%o observed in studies with young healthy volunteers (9, 11, 17). In addition to the possibility of an enhanced inhibitory response to ciprofloxacin in the elderly, drug interactions are more likely in this age group as a result of the large number of medications consumed. Therefore, the purpose of this study was to prospectively test the hypothesis that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin is greater in elderly than in young individuals by comparing effects on the disposition of antipyrine and its major metabolites. * Corresponding author. t Present address: Department of Pharmacy, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada. t Present address: Glaxo Canada, Inc., Toronto, Ontario M8Z

5S6, Canada.

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VOL. 35, 1991

-J

Young-Ciprofloxacin( 0-0 ) Elderly-Ciprofloxacin( A-A )

A

20

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0 0

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2

5

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0

0~ C

2

0

5

10

15

20

25

30

35

0 A

40

45

50

Time (hours) FIG. 1. Mean concentrations of antipyrine in sera of young and elderly subjects under control conditions and with ciprofloxacin treatment.

acin concentration was determined by high-performance liquid chromatography, using the method of Fong et al. (5). Data analysis. Area under the antipyrine serum concentration-time curve from zero to infinity was determined by LaGrange polynomial interpolation, using the computer program LAGRAN (13). Antipyrine oral clearance was calculated by dividing the administered dose by the area under the antipyrine serum concentration-time curve. This calculation assumes that the absorption of antipyrine is complete (21). The half-life was calculated by linear regression analysis of the serum antipyrine concentration data. Formation clearance for each of the three antipyrine metabolites was determined by multiplying antipyrine oral clearance by the molar fraction of the administered dose excreted as metabolite (2). Two subjects, one in each group, were excluded from the analysis of metabolite formation clearance because of incomplete urine collection. A two-factor analysis of variance with repeated measures on one factor was used to statistically determine the effect of age and ciprofloxacin on the oral clearance and half-life of antipyrine as well as the formation clearance of each metabolite. Percent change in each of these parameters with ciprofloxacin was compared between young and elderly subjects, using an unpaired Student t test. The unpaired Student t test was also used to compare ciprofloxacin concentrations between the young and elderly subjects. A value of P < 0.05 was considered statistically significant. RESULTS

Ciprofloxacin concentrations 8 h following concomitant administration of ciprofloxacin and antipyrine were 0.82 ± 0.27 mg/liter in the young subjects and 1.27 ± 0.55 mg/liter (mean ± standard deviation) in the elderly group (P < 0.05). However, antipyrine concentrations in serum were similar under control conditions in young and elderly subjects and increased in both groups with ciprofloxacin (Fig. 1). Pharmacokinetic parameters are tabulated in Table 1. Baseline oral clearance of antipyrine was not different between the young and elderly subjects. Administration of ciprofloxacin decreased the average clearance by 23.3% in the young subjects and 27.9% in the elderly subjects (P < 0.05 in both groups). However, the magnitude of inhibition was not significantly different between the groups. The percentage decrease in clearance ranged from 2.8 to 40.6% in the young

131

subjects and from 13.8 to 49.0% in the elderly subjects (Fig. 2), with one young subject and two elderly subjects experiencing decreases of more than 40%. There was no relationship between ciprofloxacin concentration and the percent decrease in antipyrine clearance (r = 0.24, not significant). Percent decrease in antipyrine oral clearance was highly correlated with baseline clearance in the young subjects (r = 0.81, P < 0.05) but not in the elderly group (r = 0.13). Changes in half-life were similar to those observed for oral clearance. The percentage of the antipyrine dose recovered in the urine as 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, norantipyrine, and parent compound was not significantly different under baseline conditions (42.7%) or following ciprofloxacin treatment (41.5%) in either group. In addition, the renal clearance of antipyrine was not altered by ciprofloxacin. Table 2 shows the formation clearance for each metabolite as well as the average percentage decrease. Ciprofloxacin significantly decreased the formation clearance of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine in both age groups, with no significant differences observed between the groups in formation of these metabolites under either control conditions or following ciprofloxacin treatment. However, ciprofloxacin treatment resulted in a significant lowering in norantipyrine formation clearance from control values in the elderly subjects only. DISCUSSION Antipyrine is a frequently used substrate for assessing the effect of various factors on hepatic oxidative drug metabolism. It is well suited for this purpose because of its rapid and complete oral absorption, minimal binding to serum proteins, and elimination by oxidative metabolism at a rate dependent on the activity of the cytochrome P-450 mixedfunction oxidase system (21). In addition, it is metabolized by several different metabolic pathways involving at least two different isozymes of cytochrome P-450 (20). Examining the formation of antipyrine metabolites allows an assessment of the impact of an inhibitor on individual isozymes, data which has not been previously reported for ciprofloxacin. Furthermore, antipyrine is a well-tolerated compound, making it an ideal substrate for administration to healthy volunteers, particularly elderly subjects who may be more sensitive to the adverse effects of other commonly used substrates such as theophylline. The results of this study demonstrate that ciprofloxacin significantly decreases the oral clearance of antipyrine. The magnitude of inhibition (23.3% in young subjects and 27.9% in elderly subjects) was somewhat lower than that reported by Ludwig et al. (8), who observed a 35% decrease in antipyrine clearance in 15 subjects aged 25 to 82 years. The relationship between age and the degree of inhibition was not reported by these investigators. Our data are also consistent with studies demonstrating an average decrease in theophylline clearance of 20 to 30% with ciprofloxacin (9, 11, 17). These reports suggest that ciprofloxacin is one of the more potent inhibitors of oxidative metabolism in clinical use today, with the magnitude of inhibition being roughly comparable to that of cimetidine (4, 22). Baseline antipyrine clearance was identical in the young and elderly subjects in this study, in contrast to 25 to 30% lower clearances in the elderly reported in studies such as that of Posner et al. (10). The reason for this difference is unclear, particularly since we observed the same decrease (18%) as these investigators in combined formation clear-

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ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1. Antipyrine pharmacokinetics in young and elderly subjects before and after ciprofloxacin Oral clearance

Age Subject

(yr)

Young 1 2 3 4 5 6 7 8 9 10 11 12 13

25 32 34 33 24 24 24 24 26 27 27 23 25

0.33 0.32 0.52 0.39 0.34 0.39 0.35 0.64 0.51 0.44 0.38 0.53 0.49

26.8 3.6

72 75 74 65 68 67 73 68 82

Mean SD

Elderly 1 2 3 4 5 6 7 8 9

a

Control

Mean 71.6 SD 4.9 Significantly different from control.

Ciprofloxacin

0.31 0.29 0.38 0.35 0.28 0.31 0.34 0.38 0.34 0.28 0.30 0.41 0.38

14.9 16.6 10.6 11.4 16.0 13.6 18.3 10.8 10.7 13.2 13.9 13.3 10.5

15.9 17.8 15.8 14.3 20.2 18.8 15.7 14.8 15.7 20.7 19.3 15.9 13.4

0.43 0.09

0.33a 0.04

13.4 2.5

16.8a 2.3

0.41 0.48 0.38 0.29 0.63 0.31 0.37 0.53 0.47

0.35 0.39 0.20 0.25 0.52 0.22 0.30 0.27 0.30

11.6 10.0 12.4 18.7 8.5 12.7 10.4 9.1 8.9

12.3 11.9 22.6 20.3 10.4 19.2 17.8 16.0 13.8

0.43 0.10

0.31a 0.09

11.4 3.1

16.0a 4.2

effect bteing in formation of norantipyrine. Also of interest is the high correlation between baseline antipyrine clearance and the magnitude of inhibition produced in young subjects. Koup elt al. (6) recently reported that inhibition of theophylline cle;arance by another quinolone, enoxacin, was more significamnt in subjects with an initial theophylline clearance over 50 ml/min. In our subjects, clearance decreased by

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ance of antipyrine metabolites in the elderly, with the largest

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(ml/min/kg) Ciprofloxacin

. 0.7

Baseline Antipyrine Clearance (mi/min/ kg) 2.i Relationship between the percentage decrease in antipyclearance with ciprofloxacin and baseline clearance.

29.7% in subjects with a baseline antipyrine clearance over 0.45 mUlmin/kg (n = 9) and by only 19.1% in the other subjects. Although we are unaware of a mechanistic explanation, this would suggest that magnitude of inhibition could be predicted to some extent. However, we did not find that a significant relationship between inhibition and baseline clearance existed in the elderly subjects, perhaps because the smaller number of data points in this group makes the correlation more susceptible to influence from one or two aberrant points. The mean percentage decrease in antipyrine clearance produced by ciprofloxacin was not significantly different between young and elderly subjects in this study. This is consistent with studies showing that cimetidine produces similar inhibition of both antipyrine (4) and theophylline (22) in young and elderly individuals. However, it does not explain the previous reports (12, 15, 19) of exaggerated inhibitory effects of ciprofloxacin in some elderly patients. We believe that this discrepancy may be related to the variability in degree of inhibition to be expected in a typical heterogeneous patient population and to the selective bias in published case reports. We observed 3 subjects (of 22 studied) who had decreases in clearance of more than 40%. Similarly, Nix et al. (9) reported that ciprofloxacin reduced theophylline clearance by more than 40%o in three of eight young subjects. Since these decreases in clearance of more than 40% are comparable to the degree of inhibition in published case reports, the latter may simply represent the upper end of the range of inhibition to be expected with this

VOL. 35, 1991

AGE AND INHIBITION OF METABOLISM BY CIPROFLOXACIN

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TABLE 2. Mean formation clearance of antipyrine metabolites Metabolite

Treatment

Mean formation clearance (SD) (ml/min/kg)a

4-Hydroxyantipyrine

Control Ciprofloxacin

Young 0.096 (0.030) 0.066b (0.011)

Norantipyrine


0.066 (0.020) 0.059 (0.016)

3-Hydroxymethylantipyrine

Elderly 0.087 (0.031) 0.053b (0.027) 0.047 (0.023)

0.033b,c (0.018)


0.024 (0.008) 0.019 (0.007) 0.015b (0.003) 0.014b (0.011) a The values for average percent decrease of antipyrine metabolites were as follows: for 4-hydroxyantipyrine, 31.3 and 39.0 for young and elderly subjects, respectively; for norantipyrine, 10.6 and 29.8 for young and elderly subjects, respectively; for 3-hydroxymethylantipyrine, 37.5 and 26.3 for young and elderly subjects, respectively. b Statistically significant (P < 0.05) compared with control. c

Statistically significant (P < 0.05) compared with young subjects.

drug. Although case reports can be useful, patients who experience average inhibition of drug metabolism when placed on ciprofloxacin will not be reported in the literature. Therefore, the magnitude of inhibition in oxidative metabolism becomes exaggerated. In addition, it is not surprising that case reports tend to involve elderly patients, since we suspect that the majority of patients receiving ciprofloxacin in the hospital are elderly. One possible reason for expecting greater inhibition of metabolism in elderly subjects is that pharmacokinetic studies have indicated that the renal clearance of ciprofloxacin is reduced and ciprofloxacin concentrations in serum are elevated in the elderly (7). We also observed that ciprofloxacin concentrations were 57% higher (on average) in the elderly than in the young subjects. A study with enoxacin suggests that inhibition is dose dependent (and presumably concentration dependent) (14). However, there are no reported studies for ciprofloxacin examining the relationship between drug concentration in serum and inhibition, and in this study (over a relatively small concentration range), there was no statistically significant relationship between these parameters. It is possible that a 50% increase in ciprofloxacin concentration in serum is not sufficient to produce a detectable increase in the magnitude of inhibition with this drug. Certainly, there is no clear trend in the literature to suggest that studies which have used 750-mg doses of ciprofloxacin report more inhibition than studies like this one and that of Ludwig et al. (8), in which 500-mg doses have been used. It is also possible that the patients previously reported to show enhanced inhibition had ciprofloxacin concentrations in serum which were elevated to a greater extent than observed here or in other pharmacokinetic studies in which relatively healthy elderly individuals have been studied. The mean formation clearance for each of the antipyrine metabolites was decreased after pretreatment with ciprofloxacin in both age groups. The only exception to this was the formation of norantipyrine, accounting for 15 to 20% of the overall clearance of antipyrine, which decreased in the elderly but not in the young subjects (Table 2). If confirmed, this observation of less inhibition of norantipyrine formation in young subjects could be important when drugs predominantly metabolized by the isozyme involved are coadministered with ciprofloxacin. It is interesting to note that although theophylline is at least partially metabolized by the same isozymes as antipyrine, previous reports suggest that the metabolism of theophylline is most highly correlated

with the formation of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine rather than norantipyrine (16). The results of this study suggest that the elderly are not, on average, more susceptible to the inhibitory effects of ciprofloxacin on oxidative drug metabolism. However, ciprofloxacin will produce in some patients, irrespective of age, large (greater than 40%) decreases in the clearance of drugs which depend on oxidative metabolism for elimination from the body. Careful clinical monitoring for elevated drug concentrations and adverse effects is required when using ciprofloxacin in combination with such compounds. ACKNOWLEDGMENTS We are grateful to David Greenblatt for performing the analysis of antipyrine and metabolites in urine and to Arthur Vandenbroucke (Department of Clinical Biochemistry, University of Toronto, and St. Michael's Hospital, Toronto, Canada) for measuring ciprofloxacin concentrations. This work was supported in part by a Wayne State University Biomedical Research Support Grant. Support for Nancy Waite was provided by a Medical Research Council of Canada Fellowship. REFERENCES 1. Blyden, G. T., B. W. LeDuc, and D. J. Greenblatt. 1986. Large theophylline requirements due to high theophylline clearance: verification by the antipyrine test. Pharmacology 32:226-231. 2. Cummings, A. J., B. K. Martin, and G. S. Park. 1967. Kinetic considerations relating to the accrual and elimination of drug metabolites. Br. J. Pharmacol. 29:136-149. 3. Edwards, D. J., S. K. Bowles, C. K. Svensson, and M. J. Rybak. 1988. Inhibition of drug metabolism by quinolone antibiotics. Clin. Pharmacokinet. 15:194-204. 4. Feely, J., L. Pereira, E. Guy, and N. Hockings. 1984. Factors affecting the response to inhibition of drug metabolism by cimetidine-dose response and sensitivity of elderly and induced subjects. Br. J. Clin. Pharmacol. 17:77-81. 5. Fong, I. W., W. H. Ledbetter, A. C. Vandenbroucke, M. Simbul, and V. Rahm. 1986. Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob. Agents Chemother. 29: 405-408. 6. Koup, J. R., R. D. Toothaker, E. Posvar, A. J. Sedman, and W. A. Colburn. 1990. Theophylline dosage adjustment during enoxacin coadministration. Antimicrob. Agents Chemother. 34: 803-807. 7. LeBel, M., G. Barbeau, M. G. Bergeron, D. Roy, and F. Vallee. 1986. Pharmacokinetics of ciprofloxacin in elderly subjects. Pharmacotherapy 6:87-91. 8. Ludwig, E., E. Szekely, A. Csida, and H. Graber. 1988. The effect of ciprofloxacin on antipyrine metabolism. J. Antimicrob.

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