EFFECT OF THEADDITION OF CIPROFLOXACIN ON THEOPHYLLINE PHARMACOKINETICS IN SUBJECTS INHIBITED BY CIMETIDINE Robin L. Davis, Ronald W. Quenzer, H. William Kelly, and J. Robert Powell
Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, little data exist on the effects of combinations of inhibiting agents. The purpose of this study was to investigate the effect of the addition of a second hepatic oxidative enzyme inhibitor on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor. OBJECTIVE:
In a randomized crossover sequence, subjects received theophylline 5 mg/kg on day 6 of therapy with cimetidine 2400 mg/d, ciprofloxacin I g/d, both drugs, or while drug-free.
DESIGN:
SErnNG: National Institutes of Health-funded General Clinical Research Center. PARTICIPANTS:
Eight normal volunteers (6 men, 2 women; mean age
25.2 y). Theophylline pharmacokinetic parameters after each treatment were determined by model independent pharmacokinetic analysis. Statistical analysis of the data for differences between treatments was assessed by ANOVA for repeated measures.
OUTCOME MEASURES:
RESEARCH: When administered alone, ciprofloxacin and cimetidine caused a significant increase in theophylline elimination half-life and a decrease in clearance. Theophylline elimination half-life was significantly longer during combined therapy compared with either drug alone. Theophylline clearance was lower during combined treatment, although this relationship did not reach statistical significance.
The addition of a second enzyme inhibitor in subjects receiving maximally inhibiting doses of cimetidine can produce a further decrease in the hepatic metabolism of drugs that are metabolized by the cytochrome P-450 microsomal enzyme system. As cimetidine and ciprofloxacin are frequently used together for a variety of common clinical indications, clinicians should be aware of this drug interaction and should consider that a similar effect may occur when other enzyme inhibitors are used concomitantly. CONCLUSIONS:
Ann Pharmacother1992;26: 11-3.
in the body for drug metabolism. In general, compounds are made more water soluble to facilitate their excretion in the urine. In phase 1 oxidative reactions, there is the addition of a polar group such as a hydroxyl or deletion of a nonpolar group by oxidation, reduction, or hydrolysis" These reactions are carried out primarily by the cytochrome P-450 hepatic microsomal oxidative enzyme system. The production of en-
THE LIVER IS THE MOST IMPORTANT SITE
ROBIN L. DAVIS, Pharm.D., is an Associate Professor, College of Pharmacy; RONALD W. QUENZER, M.D., is an Associate Professor, Division ofinfectious Diseases, School of Medicine; H. WILLIAM KELLY, Pharm.D., is a Professor of Pharmacy and Pediatrics, University of New Mexico, Albuquerque. NM; and J. ROBERT POWELL, Pharm.D., is the Director of Pharmacokinetics, Glaxo, Inc., Research Triangle Park, NC. Reprints: Robin L. Davis, Pharm.D., Associate Professor, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131. Funded by a grant from Glaxo Inc. and General Clinical Research Program, DRR, NIH 5 MOl RROO997 1989.
zymes in this system can be induced by enzyme inducers such as phenobarbital, resulting in subtherapeutic serum concentrations and increased dosage requirements of coadministered drugs.' The activity of these enzymes also can be inhibited in a competitive or noncompetitive manner by a variety of compounds. The inhibitor of hepatic cytochrome P-450 that has been the most thoroughly investigated is the histamine H2antagonist cimetidine. Clinical studies have shown that cimetidine inhibits the metabolism of other drugs metabolized by phase 1 oxidation reactions by 20-60 percent, resulting in enhanced serum concentrations and clinically important toxic reactions.' Theophylline is a methylxanthine bronchodilator widely used in the treatment of asthma and other respiratory diseases. Its clearance is used as a marker of microsomal enzyme activity, as 85-90 percent of an administered dose is metabolized by hepatic cytochrome P-450-mediated Ndemethylation and 8-hydroxylation.4 Cimetidine has been shown to inhibit theophylline metabolism by approximately 30 percent.' The inhibitory effect of cimetidine on the metabolism of theophylline and other drugs is dose-dependent, with higher cimetidine doses causing greater inhibition. Feely et al. found mean reductions in theophylline clearance of 16.8 and 26.3 percent when normal volunteers were given cimetidine 400 and 800 mg/d, respectively.' This dose-dependency also occurs with other drugs. Similar dose-dependent inhibitory effects on phenytoin metabolism by cimetidine were reported in an investigation by Bartle et al," The upper limit of inhibition occurs at cimetidine dosages of 1200-2400 mg/d. Powell et al. studied the dependency of cimetidine dose on the inhibition of theophylline clearance in 12 normal volunteers. Control theophylline clearance in the subjects was 51.3 ± 19.4 mlzh-kg. Cimetidine dosages of 1200 mg/d resulted in a statistically significant decrease in clearance (32.8 ± 10.0 mlzh-kg). Administration of higher cimetidine dosages (2400 mg/d) did not produce a further reduction in clearance (31.5 ± 14.3
ml.zh-kg),? Ciprofloxacin is a fluoroquinolone antibiotic that decreases theophylline clearance, with reports of up to a threefold increase in theophylline serum concentrations in patients during ciprofloxacin coadministration.v' These results have been confirmed in controlled crossover studies in healthy volunteers and in patients with chronic obstructive lung disease, with a reported 26-30 percent decrease in theophylline clearance and a 26-35 percent increase in half-life after administration of ciprofloxacin 1-1.5 g/d. to·12 Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, few data exist on the effects of combinations of
The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at CARLETON UNIV on June 18, 2015
1992 January, Volume 26 •
11
inhibiting agents. The purpose of this study was to investigate whether the administration of a hepatic oxidative enzyme inhibitor would produce an additive, synergistic, or antagonistic effect on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor in this investigation. Methods Eight normal volunteers (six men, two women) with a mean age of 25.2 years participated in the study. All were nonsmokers and had normal physical examinations and hematologic and biochemistry studies. None of the subjects had respiratory disease or required theophylline treatment. This investigation was approved by the human research review committee, the investigational review board at our institution. Subjects consented in writing to the study after being provided thorough explanation of what was involved and the risks of the study. In a randomized, crossover, latin-square design, the clearance of theophylline was determined after the subjects received each of the following drug regimens: (I) while drug free, (2) on day 6 of taking cimetidine (Tagamet) 600 mg qid, (3) on day 6 of taking ciprofloxacin (Cipro) 500 mg bid, and (4) on day 6 of taking cimetidine 600 mg qid and ciprofloxacin 500 mg bid. One of the subjects took the antihistamine terfenadine 60 mg bid throughout the study for prevention of symptoms of seasonal rhinitis. This drug has been shown to have no effect on theophylline pharmacokinetics." The other subjects abstained from taking prescription or overthe-eounter drugs and avoided foods known to affect hepatic microsomal enzyme activity (e.g., charbroiled meats) while participating in the study. They also avoided caffeine-containing foods and beverages and ethanol for 72 hours prior to each administration of theophylline. The periods of study were separated by a seven-day interval during which the subjects received no drugs. On day 6 of drug administration or while drug-free, the subjects were administered theophylline 5 mg/kg as the ethylenediamine salt (aminophylline) by intravenous infusion over 30 minutes. Blood samples were collected just before, immediately after, and at 0, 0.25,0.5,0.75, I, 1.5,2,3,4,6,8,12, and 24 hours after aminophylline administration. Samples were stored at _30°C until the day of assay. Samples were analyzed for theophylline concentration by enzymatic immunoassay utilizing a centrifugal analyzer (Monarch 2000, Instrumentation Laboratories). This assay is linear between 0.1 and 35.0 ug/ml, with a lower limit of detection of O. I ug/ml., The interday and intraday coefficients of variation were 3.8 and 4.5 percent, respectively, at 5 ug/ml., 2.2 and 3.0 percent, respectively, at 15 j..Lg/mL, and 2.7 and 3.7 percent, respectively, at 30 ug/ml., The data were analyzed by model-independent pharmacokinetic analysis'tfor theophylline parameters with and without ciprofloxacin and/or cimetidine coadministration. Statistical analysis of the data for differences between treatments was performed by analysis of variance for repeated measures. Parameters found to change significantly were further analyzed for differences between treatments using Duncan's range test." A p value of
Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, little data exist on the effects of combinations of inhibiting agents. The purpose of this study was to investigate the effect of the addition of a second hepatic oxidative enzyme inhibitor on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor. OBJECTIVE:
In a randomized crossover sequence, subjects received theophylline 5 mg/kg on day 6 of therapy with cimetidine 2400 mg/d, ciprofloxacin I g/d, both drugs, or while drug-free.
DESIGN:
SErnNG: National Institutes of Health-funded General Clinical Research Center. PARTICIPANTS:
Eight normal volunteers (6 men, 2 women; mean age
25.2 y). Theophylline pharmacokinetic parameters after each treatment were determined by model independent pharmacokinetic analysis. Statistical analysis of the data for differences between treatments was assessed by ANOVA for repeated measures.
OUTCOME MEASURES:
RESEARCH: When administered alone, ciprofloxacin and cimetidine caused a significant increase in theophylline elimination half-life and a decrease in clearance. Theophylline elimination half-life was significantly longer during combined therapy compared with either drug alone. Theophylline clearance was lower during combined treatment, although this relationship did not reach statistical significance.
The addition of a second enzyme inhibitor in subjects receiving maximally inhibiting doses of cimetidine can produce a further decrease in the hepatic metabolism of drugs that are metabolized by the cytochrome P-450 microsomal enzyme system. As cimetidine and ciprofloxacin are frequently used together for a variety of common clinical indications, clinicians should be aware of this drug interaction and should consider that a similar effect may occur when other enzyme inhibitors are used concomitantly. CONCLUSIONS:
Ann Pharmacother1992;26: 11-3.
in the body for drug metabolism. In general, compounds are made more water soluble to facilitate their excretion in the urine. In phase 1 oxidative reactions, there is the addition of a polar group such as a hydroxyl or deletion of a nonpolar group by oxidation, reduction, or hydrolysis" These reactions are carried out primarily by the cytochrome P-450 hepatic microsomal oxidative enzyme system. The production of en-
THE LIVER IS THE MOST IMPORTANT SITE
ROBIN L. DAVIS, Pharm.D., is an Associate Professor, College of Pharmacy; RONALD W. QUENZER, M.D., is an Associate Professor, Division ofinfectious Diseases, School of Medicine; H. WILLIAM KELLY, Pharm.D., is a Professor of Pharmacy and Pediatrics, University of New Mexico, Albuquerque. NM; and J. ROBERT POWELL, Pharm.D., is the Director of Pharmacokinetics, Glaxo, Inc., Research Triangle Park, NC. Reprints: Robin L. Davis, Pharm.D., Associate Professor, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131. Funded by a grant from Glaxo Inc. and General Clinical Research Program, DRR, NIH 5 MOl RROO997 1989.
zymes in this system can be induced by enzyme inducers such as phenobarbital, resulting in subtherapeutic serum concentrations and increased dosage requirements of coadministered drugs.' The activity of these enzymes also can be inhibited in a competitive or noncompetitive manner by a variety of compounds. The inhibitor of hepatic cytochrome P-450 that has been the most thoroughly investigated is the histamine H2antagonist cimetidine. Clinical studies have shown that cimetidine inhibits the metabolism of other drugs metabolized by phase 1 oxidation reactions by 20-60 percent, resulting in enhanced serum concentrations and clinically important toxic reactions.' Theophylline is a methylxanthine bronchodilator widely used in the treatment of asthma and other respiratory diseases. Its clearance is used as a marker of microsomal enzyme activity, as 85-90 percent of an administered dose is metabolized by hepatic cytochrome P-450-mediated Ndemethylation and 8-hydroxylation.4 Cimetidine has been shown to inhibit theophylline metabolism by approximately 30 percent.' The inhibitory effect of cimetidine on the metabolism of theophylline and other drugs is dose-dependent, with higher cimetidine doses causing greater inhibition. Feely et al. found mean reductions in theophylline clearance of 16.8 and 26.3 percent when normal volunteers were given cimetidine 400 and 800 mg/d, respectively.' This dose-dependency also occurs with other drugs. Similar dose-dependent inhibitory effects on phenytoin metabolism by cimetidine were reported in an investigation by Bartle et al," The upper limit of inhibition occurs at cimetidine dosages of 1200-2400 mg/d. Powell et al. studied the dependency of cimetidine dose on the inhibition of theophylline clearance in 12 normal volunteers. Control theophylline clearance in the subjects was 51.3 ± 19.4 mlzh-kg. Cimetidine dosages of 1200 mg/d resulted in a statistically significant decrease in clearance (32.8 ± 10.0 mlzh-kg). Administration of higher cimetidine dosages (2400 mg/d) did not produce a further reduction in clearance (31.5 ± 14.3
ml.zh-kg),? Ciprofloxacin is a fluoroquinolone antibiotic that decreases theophylline clearance, with reports of up to a threefold increase in theophylline serum concentrations in patients during ciprofloxacin coadministration.v' These results have been confirmed in controlled crossover studies in healthy volunteers and in patients with chronic obstructive lung disease, with a reported 26-30 percent decrease in theophylline clearance and a 26-35 percent increase in half-life after administration of ciprofloxacin 1-1.5 g/d. to·12 Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, few data exist on the effects of combinations of
The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at CARLETON UNIV on June 18, 2015
1992 January, Volume 26 •
11
inhibiting agents. The purpose of this study was to investigate whether the administration of a hepatic oxidative enzyme inhibitor would produce an additive, synergistic, or antagonistic effect on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor in this investigation. Methods Eight normal volunteers (six men, two women) with a mean age of 25.2 years participated in the study. All were nonsmokers and had normal physical examinations and hematologic and biochemistry studies. None of the subjects had respiratory disease or required theophylline treatment. This investigation was approved by the human research review committee, the investigational review board at our institution. Subjects consented in writing to the study after being provided thorough explanation of what was involved and the risks of the study. In a randomized, crossover, latin-square design, the clearance of theophylline was determined after the subjects received each of the following drug regimens: (I) while drug free, (2) on day 6 of taking cimetidine (Tagamet) 600 mg qid, (3) on day 6 of taking ciprofloxacin (Cipro) 500 mg bid, and (4) on day 6 of taking cimetidine 600 mg qid and ciprofloxacin 500 mg bid. One of the subjects took the antihistamine terfenadine 60 mg bid throughout the study for prevention of symptoms of seasonal rhinitis. This drug has been shown to have no effect on theophylline pharmacokinetics." The other subjects abstained from taking prescription or overthe-eounter drugs and avoided foods known to affect hepatic microsomal enzyme activity (e.g., charbroiled meats) while participating in the study. They also avoided caffeine-containing foods and beverages and ethanol for 72 hours prior to each administration of theophylline. The periods of study were separated by a seven-day interval during which the subjects received no drugs. On day 6 of drug administration or while drug-free, the subjects were administered theophylline 5 mg/kg as the ethylenediamine salt (aminophylline) by intravenous infusion over 30 minutes. Blood samples were collected just before, immediately after, and at 0, 0.25,0.5,0.75, I, 1.5,2,3,4,6,8,12, and 24 hours after aminophylline administration. Samples were stored at _30°C until the day of assay. Samples were analyzed for theophylline concentration by enzymatic immunoassay utilizing a centrifugal analyzer (Monarch 2000, Instrumentation Laboratories). This assay is linear between 0.1 and 35.0 ug/ml, with a lower limit of detection of O. I ug/ml., The interday and intraday coefficients of variation were 3.8 and 4.5 percent, respectively, at 5 ug/ml., 2.2 and 3.0 percent, respectively, at 15 j..Lg/mL, and 2.7 and 3.7 percent, respectively, at 30 ug/ml., The data were analyzed by model-independent pharmacokinetic analysis'tfor theophylline parameters with and without ciprofloxacin and/or cimetidine coadministration. Statistical analysis of the data for differences between treatments was performed by analysis of variance for repeated measures. Parameters found to change significantly were further analyzed for differences between treatments using Duncan's range test." A p value of
