Comparison Pharmacokinetics and Vincent
F’. Mauro,
PharmD,
Laurie
of Pentoxifylline Between Smokers Nonsmokers S. Mauro,
PharmD,
and
John
H. Hageman,
MD
Pentoxifylline is a synthetic xanthine derivative and is hepatically cleared. The natural dimethylxanthines theobromine and theophylline have been shown to have enhanced metabolism in smokers when compared with nonsmokers. Subsequently, the effect of smoking on pentoxifylline plasma concentrations was investigated. Twenty healthy volunteers (10 smokers and 10 nonsmokers) received pentoxifylline 400 mg as a controlledrelease tablet every 8 hours for 17 doses. Several blood samples were collected for 8 hours after the final dose. These samples were assayed for pentoxifylline and its metabolites. The mean values of the smokers were compared with those of the nonsmokers. With respect to pentoxifylline, no statistically significant differences in maximum concentration and time of maximum concentration were observed between the two groups. Although no statistical differences in plasma concentrations and area-under-the-curve at steady state (AUC,,) were observed, the oral clearance of pentoxifylline among the smokers (.22 ± .08 L/minute/kg) was significantly greater (P < .05) than that among the nonsmokers (0.15 ± 0.06 L/minute/kg) when corrected for body weight. With respect to the pentoxifylline metabolite I-(5-hydroxy-hexyl)-3,7-dimethylxanthine (MI), the maximum concentration and AUCSS of the smokers were significantly decreased when compared with the nonsmokers. The ALICSS of the smokers was 1438 ± 819 ng ‘ hour/mL and of the nonsmokers was 2864 ± 1375 ng hour/mL (P < .02). The results of this trial suggest that smoking tends to reduce pentoxifylline plasma concentrations and significantly reduces MI plasma concentrations.
Pentoxifylline [1 -(5-oxoheyxl)-3,7-dimethylxanthine] is a synthetic xanthine derivative. Clinically, pentoxifylline has been proven to be effective in the treatment of intermittent claudication.1’2 Pentoxifylline is also being investigated in the treatment of cerebrovascular, ischemic heart, and sickle cell diseases.3 Pentoxifylline is hepatically metabolized by oxidation to six renally excreted metabolites.4 The two most predominant are 1-(4-carboxybutyl)3,7-dimethylxanthine (MIV) and I-(3-carboxypropyl)-3,7-dimethylxanthine (MV). In addition, pentoxifylline is reduced extrahepatically to form an intermediate metabolite known as 1-(5-hydroxyFrom the College of Pharmacy of Toledo, and the Department
(Drs. V. Mauro and L. Mauro), University of Pharmacy, Medical College of Ohio;
and the Department of Surgery (Dr. Hageman), Medical College of Ohio, Toledo, Ohio. This study was funded by a grant from HoechstRoussel PharmD, 43606.
1054
pharmaceuticals. Address University of Toledo, 2801
5
J Clin Pharmacol
for reprints: West Bancroft
1992;32:1054-1058
Vincent Street,
F. Mauro, Toledo, OH
(MI), which is either metabolized further or converted back to the parent compound.’ Cigarette smoking increases the hepatic metabolism of the natural dimethyixanthines theobromine and theophylline.6’7 The purpose of this study was to investigate the effects of smoking on pentoxifylline hexyl)-3,7-dimethylxanthine
pharmacokinetics
in
healthy
volunteers.
METHODS study was approved by the committee on human research. All volunteers passed a physical examination and signed written informed consent before entry into the study. Ten healthy male subjects between the ages of 21 and 31 years (mean, 25 years) and weighing between 141 and 200 pounds (mean, 174 pounds) who had never smoked regularly and had not smoked at all within the last 3 years were entered into the study as nonsmokers. Ten healthy male subjects between the ages of 20 and 38 (mean,
This
?N1
UAffYLLINt
l-’IIAtMAUUXINI1l1;s
28 years) and weighing between 122 and 170 pounds (mean, 148 pounds) who had smoked at least one pack of cigarettes per day for at least I year were entered into the study as smokers. All subjects reported no heavy alcohol consumption. None of the subjects had a history of cardiovascular, liver, renal, or gastrointestinal disease, or hypersensitivity to pentoxifylline, theophylline, theobromine, or caffeine. None were currently taking any medications. Subjects were instructed to follow a methylxanthine-free and alcohol-free diet starting 2 days before and continuing throughout the study period. Each subject received pentoxifylline (Trental, HoechstRoussel, Somerville, NJ, lot RP 5475) 400 mg every 8 hours for 6 days. On day 7, after an overnight fast, a series of 7-cc blood samples were drawn immediately before and .25, .5, .75, 1, 1.5, 2, 4, 6, and 8 hours after the morning dose of pentoxifylline. Subjects fasted for 4 hours after the morning dose. Blood samples were collected through a heparin lock into heparinized vacuum tubes designed for trace element measurements (Vacutainer tubes, dark blue stopper, #6527, Bectin-Dickinson, Rutherford, NJ), centrifuged, separated in duplicate, and frozen at -20#{176}C.Samples were analyzed for pentoxifylline, MI, MIV, and MV 6 to 10 months later using gas chromatography as described by Burrows.8 Pentoxifylline, MI, MIV, and MV have been shown to be stable up to 17 months when frozen (Personal communication: Ron Sabo, Hoechst-Roussel Pharmaceuticals, April 17, 1992). Data
IN
SMUIthItS
AND
fore, oral clearance, was calculated. For each volunteer, centration (tmax), (Gmax), AUG over (AUGSJ, and the steady state (Gay) line, MI, MIV, and using the trapezoidal following equation:
NUNSMUXFAIS
rather
total
body
clearance,
time of maximum plasma conmaximum plasma concentration one dosing interval at steady state average plasma concentration at were determined for pentoxifylMV. The AUG was calculated rule; was calculated by the G8
where T represents val. The apparent line was calculated
than
=
AUG/T
the duration of the dosing interoral clearance (CL0) of pentoxifylby the following equation: CL0
=
Dose/AUG.
For each of the above-described pharmacokinetic calculations, the means of the smokers and nonsmokers were calculated and compared with each other using the Student’s t test (two-tailed) with the level of statistical significance at P < .05. RESULTS All subjects successfully completed the study. Mean pentoxifylline and MI plasma concentrations of the smokers and nonsmokers are plotted in Figures 1 and 2, respectively. Although the plotted mean pentoxifylline concentrations for the nonsmokers tended to
Analysis 175
Because pentoxifylline is commercially available only as an oral controlled-release tablet, and an intravenous dosage form was not available to us at the time of the study, a few important aspects should be discussed. First, a pentoxifylline multiple-dose study design was chosen rather than a single-dose study to guarantee an accurate determination of area under the curve (AUC). Measurement of AUG to infinity after a single dose with controlled-release preparations is difficult because determination of the terminal phase is subject to error because of the rate-limited absorption. Beermann et al.9 observed no statistical difference between AUG to infinity and AUG over one dosing interval at steady state in patients receiving pentoxifylline 400-mg controlled-release tablets three times a day for 9 days. Use of the controlled-release preparation also prevents accurate calculation of an elimination rate constant. Finally, because of the lack of a commercially available parenteral preparation, the absolute bioavailability of pentoxifylline could not be determined; and there-
HEMATOLOGIC
AGENTS
1 L ii ..
a
Time
(hrs.)
Figure 1. Mean pentoxifylline plasma concentrations (±SEM) during a dosing interval at steady state in smokers and nonsmokers receiving pentoxifylline 400 mg every 8 hours. The asterisk indicates the result of the smoking group had a P of
F’. Mauro,
PharmD,
Laurie
of Pentoxifylline Between Smokers Nonsmokers S. Mauro,
PharmD,
and
John
H. Hageman,
MD
Pentoxifylline is a synthetic xanthine derivative and is hepatically cleared. The natural dimethylxanthines theobromine and theophylline have been shown to have enhanced metabolism in smokers when compared with nonsmokers. Subsequently, the effect of smoking on pentoxifylline plasma concentrations was investigated. Twenty healthy volunteers (10 smokers and 10 nonsmokers) received pentoxifylline 400 mg as a controlledrelease tablet every 8 hours for 17 doses. Several blood samples were collected for 8 hours after the final dose. These samples were assayed for pentoxifylline and its metabolites. The mean values of the smokers were compared with those of the nonsmokers. With respect to pentoxifylline, no statistically significant differences in maximum concentration and time of maximum concentration were observed between the two groups. Although no statistical differences in plasma concentrations and area-under-the-curve at steady state (AUC,,) were observed, the oral clearance of pentoxifylline among the smokers (.22 ± .08 L/minute/kg) was significantly greater (P < .05) than that among the nonsmokers (0.15 ± 0.06 L/minute/kg) when corrected for body weight. With respect to the pentoxifylline metabolite I-(5-hydroxy-hexyl)-3,7-dimethylxanthine (MI), the maximum concentration and AUCSS of the smokers were significantly decreased when compared with the nonsmokers. The ALICSS of the smokers was 1438 ± 819 ng ‘ hour/mL and of the nonsmokers was 2864 ± 1375 ng hour/mL (P < .02). The results of this trial suggest that smoking tends to reduce pentoxifylline plasma concentrations and significantly reduces MI plasma concentrations.
Pentoxifylline [1 -(5-oxoheyxl)-3,7-dimethylxanthine] is a synthetic xanthine derivative. Clinically, pentoxifylline has been proven to be effective in the treatment of intermittent claudication.1’2 Pentoxifylline is also being investigated in the treatment of cerebrovascular, ischemic heart, and sickle cell diseases.3 Pentoxifylline is hepatically metabolized by oxidation to six renally excreted metabolites.4 The two most predominant are 1-(4-carboxybutyl)3,7-dimethylxanthine (MIV) and I-(3-carboxypropyl)-3,7-dimethylxanthine (MV). In addition, pentoxifylline is reduced extrahepatically to form an intermediate metabolite known as 1-(5-hydroxyFrom the College of Pharmacy of Toledo, and the Department
(Drs. V. Mauro and L. Mauro), University of Pharmacy, Medical College of Ohio;
and the Department of Surgery (Dr. Hageman), Medical College of Ohio, Toledo, Ohio. This study was funded by a grant from HoechstRoussel PharmD, 43606.
1054
pharmaceuticals. Address University of Toledo, 2801
5
J Clin Pharmacol
for reprints: West Bancroft
1992;32:1054-1058
Vincent Street,
F. Mauro, Toledo, OH
(MI), which is either metabolized further or converted back to the parent compound.’ Cigarette smoking increases the hepatic metabolism of the natural dimethyixanthines theobromine and theophylline.6’7 The purpose of this study was to investigate the effects of smoking on pentoxifylline hexyl)-3,7-dimethylxanthine
pharmacokinetics
in
healthy
volunteers.
METHODS study was approved by the committee on human research. All volunteers passed a physical examination and signed written informed consent before entry into the study. Ten healthy male subjects between the ages of 21 and 31 years (mean, 25 years) and weighing between 141 and 200 pounds (mean, 174 pounds) who had never smoked regularly and had not smoked at all within the last 3 years were entered into the study as nonsmokers. Ten healthy male subjects between the ages of 20 and 38 (mean,
This
?N1
UAffYLLINt
l-’IIAtMAUUXINI1l1;s
28 years) and weighing between 122 and 170 pounds (mean, 148 pounds) who had smoked at least one pack of cigarettes per day for at least I year were entered into the study as smokers. All subjects reported no heavy alcohol consumption. None of the subjects had a history of cardiovascular, liver, renal, or gastrointestinal disease, or hypersensitivity to pentoxifylline, theophylline, theobromine, or caffeine. None were currently taking any medications. Subjects were instructed to follow a methylxanthine-free and alcohol-free diet starting 2 days before and continuing throughout the study period. Each subject received pentoxifylline (Trental, HoechstRoussel, Somerville, NJ, lot RP 5475) 400 mg every 8 hours for 6 days. On day 7, after an overnight fast, a series of 7-cc blood samples were drawn immediately before and .25, .5, .75, 1, 1.5, 2, 4, 6, and 8 hours after the morning dose of pentoxifylline. Subjects fasted for 4 hours after the morning dose. Blood samples were collected through a heparin lock into heparinized vacuum tubes designed for trace element measurements (Vacutainer tubes, dark blue stopper, #6527, Bectin-Dickinson, Rutherford, NJ), centrifuged, separated in duplicate, and frozen at -20#{176}C.Samples were analyzed for pentoxifylline, MI, MIV, and MV 6 to 10 months later using gas chromatography as described by Burrows.8 Pentoxifylline, MI, MIV, and MV have been shown to be stable up to 17 months when frozen (Personal communication: Ron Sabo, Hoechst-Roussel Pharmaceuticals, April 17, 1992). Data
IN
SMUIthItS
AND
fore, oral clearance, was calculated. For each volunteer, centration (tmax), (Gmax), AUG over (AUGSJ, and the steady state (Gay) line, MI, MIV, and using the trapezoidal following equation:
NUNSMUXFAIS
rather
total
body
clearance,
time of maximum plasma conmaximum plasma concentration one dosing interval at steady state average plasma concentration at were determined for pentoxifylMV. The AUG was calculated rule; was calculated by the G8
where T represents val. The apparent line was calculated
than
=
AUG/T
the duration of the dosing interoral clearance (CL0) of pentoxifylby the following equation: CL0
=
Dose/AUG.
For each of the above-described pharmacokinetic calculations, the means of the smokers and nonsmokers were calculated and compared with each other using the Student’s t test (two-tailed) with the level of statistical significance at P < .05. RESULTS All subjects successfully completed the study. Mean pentoxifylline and MI plasma concentrations of the smokers and nonsmokers are plotted in Figures 1 and 2, respectively. Although the plotted mean pentoxifylline concentrations for the nonsmokers tended to
Analysis 175
Because pentoxifylline is commercially available only as an oral controlled-release tablet, and an intravenous dosage form was not available to us at the time of the study, a few important aspects should be discussed. First, a pentoxifylline multiple-dose study design was chosen rather than a single-dose study to guarantee an accurate determination of area under the curve (AUC). Measurement of AUG to infinity after a single dose with controlled-release preparations is difficult because determination of the terminal phase is subject to error because of the rate-limited absorption. Beermann et al.9 observed no statistical difference between AUG to infinity and AUG over one dosing interval at steady state in patients receiving pentoxifylline 400-mg controlled-release tablets three times a day for 9 days. Use of the controlled-release preparation also prevents accurate calculation of an elimination rate constant. Finally, because of the lack of a commercially available parenteral preparation, the absolute bioavailability of pentoxifylline could not be determined; and there-
HEMATOLOGIC
AGENTS
1 L ii ..
a
Time
(hrs.)
Figure 1. Mean pentoxifylline plasma concentrations (±SEM) during a dosing interval at steady state in smokers and nonsmokers receiving pentoxifylline 400 mg every 8 hours. The asterisk indicates the result of the smoking group had a P of
