The Journal of International Medical Research 1990; 18: 282 - 288
Oral and Intravenous Pharmacokinetic Profiles of Doxofylline in Patients with Chronic Bronchitis E. Bologna', A. Lagana', D. Terractno', P. Boljgnari' and P. BiffignandP 'Clinical Pharmacology Unit, San Giovanni Calibita Hospital, Rome, Italy; 2Department ofIndustrial Chemistry, University of Bologna, Bologna, Italy; 3Medical Department, Research and Development, ABC Farmaceutici, Turin, Italy
Serum doxofylline concentrations were evaluated after solid-phase extraction by high-performance liquid chromatography following administration of 100 mg doxofylline given as a single intravenous dose over 10 min or 400 mg doxofylline given orally twice daily for 5 days in six and eight non-smoking, fasting, chronic bronchitic patients, respectively. Doxofylline possessed a very short distribution phase following intravenous administration, with a sustained elimination phase (half-life 1.83 ± 0.37 h). After oral administration, the peak serum doxofylline concentration was 15.21 ± 1.73 ug/ml and the mean elimination half-life was 7.01 ± 0.80 h; there was a large inter-subject variability. No side-effects were experienced by the patients during the study. KEY WORDS: Doxofylline; bronchodilator; pharmacokinetics; high-performance liquid chromatography.
INTRODUCTION
D
oxofylline (7-(1,3-dioxolan-2-ylmethyl)theophylline, Fig. I) is a new xanthinederivativewithan antibronchospastic activity equal or superior to theophylline, I despite it only having a weak affmity for adenosine AI and ~ receptors.I
Received for publication 17 May 1990; accepted 23 May 1990. Address for correspondence: Dr Paolo Biffignandi, Director, Medical Affairs, ABC Farmaceutici, Via Crescentino 25,10154 Torino, Italy.
282
Pharmacodynamic investigations in animals have demonstrated that doxofylline was able to overcome bronchoconstriction, inflammatory events (pleurisy) and thromboxane A 2 release when challenged with platelet-activating factor.' In addition, doxofylline has been shown to be effective and well tolerated after either intravenous" or oral' administration. Initialpharmacokinetic studies in healthy human volunteers have reported that after intravenous injection doxofylline had a biexponential serum concentration curve with © Copyright 1990 by Cambridge Medical Publications Ltd
Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
Doxofylline in chronic bronchitis
Fig. 1. Structure of doxofylline.
a rapid elimination a-phase of less than 20 min and total clearance, suggesting that an extrarenal component is involved in the elimination." Following oral administration of doxofylline at a dose of 400 mg, there was rapid absorption of the drug, with peak serum concentration being reached after about I h and a steady state being attained on the fourth day of treatment. Absolute bioavailability (calculated as the ratio of the area under the curve following intravenous and oral administration) was 63 ± 25%, with only one metabolite (~-hy droxymethyltheophylline),which wasdevoid of any significant pharmacological activity,? being detected in the serum and urine. The present study was designed to evaluate the pharmacokinetics of doxofylline when given either intravenously or orally in patients with chronic bronchitis.
heart disease was also present in one patient and another patient also had thyroid goitre but hormone levels were within the normal range. For the oral study, eight male patients with a mean age of 74.0 ± 7.0 years and a mean body weight of 66.0 ± 4.0 kg (no more than 15% deviation from ideal body weight) were enrolled. All subjects in this study were also non-smokers and were suffering from chronic bronchitis, with diabetes mellitus being present in two patients. No patient was allowed to take other xanthines, including those present in beverages, for at least 2 weeks before the start of the study and no other medications were allowed for 4 days before the start of treatment, except in the case of three patients who received concomitant treatment with ranitidine, calcitonin or captopril.
PATIENTS AND METHODS
Patients For the intravenous study, six patients (two males, four females) with a mean age of 59.7 ± 20.3 years and a mean body weight of 65.7 ± 11.4 kg (no more than 15% deviation from the ideal body weight) were enrolled. All subjects were non-smokers and suffered from chronic bronchitis; ischaemic
Doxofylline administration Doxofylline was administered under fasting conditions to six patients as a single intravenous dose of 100 mg over 10 min. In another eight patients, doxofylline was administered orally at dose of 400 mg taken twice daily for a total of 5 days, with administration taking place at least 3 h
283 Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
E. Bologna, A. Lagana, D. Terracino et at.
before or after a meal. All drug administrations were carefully monitored by hospital personnel. Doxofylline assay Blood samples were collected from the antecubital vein (the contralateral vein was used for the intravenous study) immediately before and 5 min - 48 h after the injection or 30 min - 6 h after the last oral dose of doxofylline, and measurement of doxofylline was performed after solid-phase extraction (Supelco). Doxofylline were measured by highperformance liquid chromatography using an S410 Perkin Elmer apparatus (Perkin Elmer, USA) equipped with a Rheodyne model 7125 valve having a 100 ul loop and with an LC95 ultraviolet detector (Perkin Elmer, USA). An LC-IlOO Laboratory Computing Integrator (Perkin Elmer, USA) was employed for peak area measurements. Chromatographic materials employed were as follows: 4.6 rom x 25 em Cl8 (Supelco) column (average particle size 5 urn); a LC18 (5 urn) reverse-phase packing; and a 4.6 rom x 2 em Supelguard (Supelco). The mobile phase consisted of 0.01 M potassium dihydrogen phosphate (to pH 3 with phosphoric acid}/methanol/ acetonitrile (87:8:5, by volume) with a flow rate of 1.2 ml/min. The chromatographic column was operated at room temperature and the eluates were monitored at 273 DID. Quantitative analysis of doxofylline was provided by comparing doxofylline/p-hydroxyethyltheophylline peak area ratios of unknown samples to those of standard curves prepared by adding known amounts of doxofylline and internal standard to the appropriate solution. Pharmacokinetic analysis Serum concentrations of doxofylline were processed using an Olivetti M20 PC computer to obtain the following parameters: semi-logarithmicconcentration - timecurve; systemic clearance; area under the curve
extrapolated to infinity; elimination halflife of the a.-phase; elimination half-life of the ~-phase; and apparent distribution volume. RESULTS
The semi-logarithmic curve of concentration versus time after a single intravenous injection of 100 mg doxofylline given over 10 min is shown in Fig. 2. The drug displayed a very short distribution phase halflife of 0.19 h followed by a more sustained elimination with a half-life of 1.83 ± 0.37 h; the systemic clearance was 6.90 ml/min-kg. The pharmacokinetic measures for intravenous doxofylline in each patient studied are presented in Table 1. Following oral administration of 400 mg doxofylline twice daily for 5 days, the peak serum doxofylline concentration at the steady state was 5.78 - 20.76 ug/ml (mean ± SD 15.21 ± 1.73 Jlg/ml), the time taken to reach maximum concentration being 1.19 ± 0.19 h. By contrast the mean elimination half-life was 7.01 ± 0.80 h; intersubject variability was 3.74 - 10.73 h. Within 6 h of administering a single dose of 4oomgdoxofylline a steady state was reached and the mean serum doxofylline concentration was 9.43 ± 1.42 Jlg/ml (Fig. 3). The pharmacokinetic measures for oral doxofylline are given in Table 2. No correlation was found between peak serumconcentration values, half-lives, values for area under curves and total clearance of doxofylline, and body weight, creatinine levels, blood pH, blood electrolyte concentrations and plasma protein concentrations and liver aminotransferases. During the study no patient complained of any side-effects following the administration of intravenous or oral doxofylline. DISCUSSION
Although their mode of action is not completely understood, xanthine derivatives have been shown to be effective in the treatment of bronchial asthma and chronic bronchitis.
284 Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
VI
tv 00
1.29
1.24
1.23
1.27
1.83 ± 0.37
3
4
5
6
Mean±SD
Cmax.' peak concentration; 1max.' time to reach Cmax:
AD
683.6 ± 197.8
514.4
547.8
1157.6
1397.6
209.2
275.0
Oral and Intravenous Pharmacokinetic Profiles of Doxofylline in Patients with Chronic Bronchitis E. Bologna', A. Lagana', D. Terractno', P. Boljgnari' and P. BiffignandP 'Clinical Pharmacology Unit, San Giovanni Calibita Hospital, Rome, Italy; 2Department ofIndustrial Chemistry, University of Bologna, Bologna, Italy; 3Medical Department, Research and Development, ABC Farmaceutici, Turin, Italy
Serum doxofylline concentrations were evaluated after solid-phase extraction by high-performance liquid chromatography following administration of 100 mg doxofylline given as a single intravenous dose over 10 min or 400 mg doxofylline given orally twice daily for 5 days in six and eight non-smoking, fasting, chronic bronchitic patients, respectively. Doxofylline possessed a very short distribution phase following intravenous administration, with a sustained elimination phase (half-life 1.83 ± 0.37 h). After oral administration, the peak serum doxofylline concentration was 15.21 ± 1.73 ug/ml and the mean elimination half-life was 7.01 ± 0.80 h; there was a large inter-subject variability. No side-effects were experienced by the patients during the study. KEY WORDS: Doxofylline; bronchodilator; pharmacokinetics; high-performance liquid chromatography.
INTRODUCTION
D
oxofylline (7-(1,3-dioxolan-2-ylmethyl)theophylline, Fig. I) is a new xanthinederivativewithan antibronchospastic activity equal or superior to theophylline, I despite it only having a weak affmity for adenosine AI and ~ receptors.I
Received for publication 17 May 1990; accepted 23 May 1990. Address for correspondence: Dr Paolo Biffignandi, Director, Medical Affairs, ABC Farmaceutici, Via Crescentino 25,10154 Torino, Italy.
282
Pharmacodynamic investigations in animals have demonstrated that doxofylline was able to overcome bronchoconstriction, inflammatory events (pleurisy) and thromboxane A 2 release when challenged with platelet-activating factor.' In addition, doxofylline has been shown to be effective and well tolerated after either intravenous" or oral' administration. Initialpharmacokinetic studies in healthy human volunteers have reported that after intravenous injection doxofylline had a biexponential serum concentration curve with © Copyright 1990 by Cambridge Medical Publications Ltd
Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
Doxofylline in chronic bronchitis
Fig. 1. Structure of doxofylline.
a rapid elimination a-phase of less than 20 min and total clearance, suggesting that an extrarenal component is involved in the elimination." Following oral administration of doxofylline at a dose of 400 mg, there was rapid absorption of the drug, with peak serum concentration being reached after about I h and a steady state being attained on the fourth day of treatment. Absolute bioavailability (calculated as the ratio of the area under the curve following intravenous and oral administration) was 63 ± 25%, with only one metabolite (~-hy droxymethyltheophylline),which wasdevoid of any significant pharmacological activity,? being detected in the serum and urine. The present study was designed to evaluate the pharmacokinetics of doxofylline when given either intravenously or orally in patients with chronic bronchitis.
heart disease was also present in one patient and another patient also had thyroid goitre but hormone levels were within the normal range. For the oral study, eight male patients with a mean age of 74.0 ± 7.0 years and a mean body weight of 66.0 ± 4.0 kg (no more than 15% deviation from ideal body weight) were enrolled. All subjects in this study were also non-smokers and were suffering from chronic bronchitis, with diabetes mellitus being present in two patients. No patient was allowed to take other xanthines, including those present in beverages, for at least 2 weeks before the start of the study and no other medications were allowed for 4 days before the start of treatment, except in the case of three patients who received concomitant treatment with ranitidine, calcitonin or captopril.
PATIENTS AND METHODS
Patients For the intravenous study, six patients (two males, four females) with a mean age of 59.7 ± 20.3 years and a mean body weight of 65.7 ± 11.4 kg (no more than 15% deviation from the ideal body weight) were enrolled. All subjects were non-smokers and suffered from chronic bronchitis; ischaemic
Doxofylline administration Doxofylline was administered under fasting conditions to six patients as a single intravenous dose of 100 mg over 10 min. In another eight patients, doxofylline was administered orally at dose of 400 mg taken twice daily for a total of 5 days, with administration taking place at least 3 h
283 Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
E. Bologna, A. Lagana, D. Terracino et at.
before or after a meal. All drug administrations were carefully monitored by hospital personnel. Doxofylline assay Blood samples were collected from the antecubital vein (the contralateral vein was used for the intravenous study) immediately before and 5 min - 48 h after the injection or 30 min - 6 h after the last oral dose of doxofylline, and measurement of doxofylline was performed after solid-phase extraction (Supelco). Doxofylline were measured by highperformance liquid chromatography using an S410 Perkin Elmer apparatus (Perkin Elmer, USA) equipped with a Rheodyne model 7125 valve having a 100 ul loop and with an LC95 ultraviolet detector (Perkin Elmer, USA). An LC-IlOO Laboratory Computing Integrator (Perkin Elmer, USA) was employed for peak area measurements. Chromatographic materials employed were as follows: 4.6 rom x 25 em Cl8 (Supelco) column (average particle size 5 urn); a LC18 (5 urn) reverse-phase packing; and a 4.6 rom x 2 em Supelguard (Supelco). The mobile phase consisted of 0.01 M potassium dihydrogen phosphate (to pH 3 with phosphoric acid}/methanol/ acetonitrile (87:8:5, by volume) with a flow rate of 1.2 ml/min. The chromatographic column was operated at room temperature and the eluates were monitored at 273 DID. Quantitative analysis of doxofylline was provided by comparing doxofylline/p-hydroxyethyltheophylline peak area ratios of unknown samples to those of standard curves prepared by adding known amounts of doxofylline and internal standard to the appropriate solution. Pharmacokinetic analysis Serum concentrations of doxofylline were processed using an Olivetti M20 PC computer to obtain the following parameters: semi-logarithmicconcentration - timecurve; systemic clearance; area under the curve
extrapolated to infinity; elimination halflife of the a.-phase; elimination half-life of the ~-phase; and apparent distribution volume. RESULTS
The semi-logarithmic curve of concentration versus time after a single intravenous injection of 100 mg doxofylline given over 10 min is shown in Fig. 2. The drug displayed a very short distribution phase halflife of 0.19 h followed by a more sustained elimination with a half-life of 1.83 ± 0.37 h; the systemic clearance was 6.90 ml/min-kg. The pharmacokinetic measures for intravenous doxofylline in each patient studied are presented in Table 1. Following oral administration of 400 mg doxofylline twice daily for 5 days, the peak serum doxofylline concentration at the steady state was 5.78 - 20.76 ug/ml (mean ± SD 15.21 ± 1.73 Jlg/ml), the time taken to reach maximum concentration being 1.19 ± 0.19 h. By contrast the mean elimination half-life was 7.01 ± 0.80 h; intersubject variability was 3.74 - 10.73 h. Within 6 h of administering a single dose of 4oomgdoxofylline a steady state was reached and the mean serum doxofylline concentration was 9.43 ± 1.42 Jlg/ml (Fig. 3). The pharmacokinetic measures for oral doxofylline are given in Table 2. No correlation was found between peak serumconcentration values, half-lives, values for area under curves and total clearance of doxofylline, and body weight, creatinine levels, blood pH, blood electrolyte concentrations and plasma protein concentrations and liver aminotransferases. During the study no patient complained of any side-effects following the administration of intravenous or oral doxofylline. DISCUSSION
Although their mode of action is not completely understood, xanthine derivatives have been shown to be effective in the treatment of bronchial asthma and chronic bronchitis.
284 Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
Downloaded from imr.sagepub.com at UNIV OF PENNSYLVANIA on April 27, 2016
VI
tv 00
1.29
1.24
1.23
1.27
1.83 ± 0.37
3
4
5
6
Mean±SD
Cmax.' peak concentration; 1max.' time to reach Cmax:
AD
683.6 ± 197.8
514.4
547.8
1157.6
1397.6
209.2
275.0
