Eur J Clin Pharmacol (1990) 38:43-45 EuropeanJouma,of (~FJ~(b:~[J @ Springer-Verlag 1990
Effect of cimetidine and ranitidine on plasma theophylline in patients with chronic obstructive airways disease treated with theophylline and corticosteroids W. B o e h n i n g Internal Medicine Clinic, Bad Lippspringe, Federal Republic of Germany
Summary. Thirty adults with chronic obstructive airways disease, who were stabilised on theophylline and corticosteroids, took part in a single blind study of the effects of cimetidine and ranitidine on plasma theophylline concentrations. The patients were randomised to receive either 150 mg ranitidine b.d. or 400 mg cimetidine b.d. for one week and serial plasma theophylline m e a s u r e m e n t s were made over a 12-hour period on two consecutive days before, during and after t r e a t m e n t with the H2-antagonist. There was a significant increase in plasma theophylline during treatment with cimetidine; two patients had levels > 20 mg. 1-1. The average increase in the theophylline concentration due to cimetidine was 32%. T h e r e was no significant change in plasma theophylline during ranitidine administration. No adverse effect occurred in any patient during the study. Key words: theophylline, ranitidine, cimetidine; obstructive lung diseases, drug interaction, plasma levels
Cimetidine interferes with the metabolism of the bronchodilator, theophylline, in man by interaction with the cytochrome P450 and P448 enzyme systems in hepatic microsomes (Jonkman and Upton, 1984; Dal Negro et al., 1984; Powell et al., 1984; Ferrari et al., 1984). As theophylline has only a narrow therapeutic plasma range (10-20 mg. 1-~), beyond which toxicity may appear, any drug interaction m a y have serious implications. Ranitidine has been shown not to interfere with theophylline metabolism in volunteers and in patients (Ruff, 1982; Powell et al., 1984; Ferrari et al., 1984; Dal Negro et al., 1984), but there are unconfirmed case reports of an interaction in chronically ill patients (Fernandez and Melewicz, 1984; G a r d n e r and Sikorski, 1984; R o y et al., 1988). The present study has examined the effect of treatment with cimetidine or ranitidine on steady state plasma theophylline concentrations in patients with chronic obstructive airways disease who were also receiving corticosteroids.
Material and methods Patients Hospital in-patients, aged 18-80 y, with severe chronic obstructive airways disease, who had been stabilised on theophylline and corticosteroids, were recruited for the study. Such patients normally also receive an H2-antagonist as prophylaxis against steroid-induced peptic ulceration. Patients were asked for their consent to participation in the study, even though the procedure formed part of the normal therapeutic investigative regimen. Excluded from the study were pregnant women and breast-feeding mothers, those with coincident renal, hepatic or other serious systemic disease, and those already established on H2-antagonists. Also excluded were smokers and those with intercurrent infection receiving tetracycline, erythromycin or aminoglycoside antibiotics, since those drugs are known to influence plasma theophylline concentrations (Jonkman and Upton, 1984).
Design A single-blind parallel group study was undertaken, in which patients were randomised to receive either ranitidine, or cimetidine. Plasma theophylline levels were estimated by staff not connected with the study, who were unaware of which treatment patients were receiving.
Materials Patients received a slow-release theophylline preparation, either Bronchoretard (Klinge) or PulmiDur forte (Astra), in an individually tailored dosage, which was kept constant throughout the study. All patients were receiving corticosteroids in individually tailored doses (29 on methylprednisolone and one on triamcinolone). Each of them received either ranitidine tablets, 150 mg b. d. or cimetidine tablets 400 mg b. d., for seven days.
Clinical Procedure Patients stabilised on theophylline and corticosteroid therapy were randomised to one of the two treatment groups, ranitidine or cometidine, by means of a predetermined code. Blood samples were taken before the study for routine haematological and biochemical screening.
W. Boehning: Cimetidine, ranitidine and theophylline kinetics
44 In addition plasma theophylline in each patient was estimated at the following times: (a) at 08.00 and 20.00 h immediately before dosing with theophylline (b) between doses of theophylline at 10.00,12.00 and 16.00 h. Patients receiving theophylline tds. took an additional dose at 12.30 h. Plasma theophylline was measured on two consecutive days, Study Days 1 and 2, before an H2-antagonist was given, again on Days 7 and 9 during H2-antagonist therapy, and finally on Days 12 and 14, after the H2-antagonist has been withdrawn. Ranitidine or cimetidine were given for one week from Study Days 3 to 9. Any clinical adverse events during the study were recorded in detail together with the treatment and outcome.
Laboratory procedures Plasma theophylline levels were determined in centrifuged, frozen samples using one calibration curve, using enzyme immuno-test kit (Emit-Test; Syva Corp, Darmstadt, Germany). The lower limit of detection was 0.5 mg. 1-1, with a variability of less than 1% on repeated determinations. Neither ranitidine nor cimetidine interfered with the test assay. The procedure is described by Gushaw et al. (1977).
Statistical Analysis Individual plasma theophylline concentrations within patients were compared using Student's t-test for paired data. Mean plasma theophylline concentrations on Days 2 and 12 were compared with those on Days 7 and 9. Mean plasma concentrations on Days 2 and 14 were also compared. The Wilcoxon rank sum test was used to compare all time points during Days 7 and 9 with those on Day 2.
Results
Patients' Thirty patients, 15 in each t r e a t m e n t group, t o o k part in the study. Details of sex, age and additional medication appear in Tables 1 and 2. The sex ratio differed in the two groups, there being m o r e females in the ranitidine group. Patients in the later group on average were also slightly older. However, those factors are unlikely to have a bearing on the results, as hepatic and renal function, as shown by laboratory biochemical data, were c o m p a r a b l e in the two t r e a t m e n t groups.
Table 1. Details of the Patients n M:F Mean age y range
Ranitidine
Cimetidine
15 5:10 55.1 42-67
15 11:4 62.3 47-74
Table 2. Additional medication (other than theophylline and corticosteroids)
Ranitidine group Patient no.
Medication
10 12 13 15 17 21 26 30
Budesonide Terbutaline, Dytide Isosorbide dinitrate, budesonide Bromazepam Digoxin, mianserin, Dytide, nifedipine Terbutaline, calcium Salbutamol Salbutamol; amoxycillin (during ranitidine)
Cimetidine group 1 6 7 8 11 14 16 18 19 22 24 27 29
Digoxin, Dytide Dytide, promethazine Budesonide Moduretic, oxazepam Amoxycillin (post-cimetidine) Budesonide Digoxin, terbutaline, bromazepam Isosorbide dinitrate Mianserin, abroxol Isosorbide dinitrate Digoxin, thiazide Ambroxol, isoniazid Digoxin, terbutaline, Dytide, glibenclamide
T h e r e was no significant difference b e t w e e n plasma theophylline concentrations in the pre- and post-cimetidine periods (Days 2 and 14). T h e mean plasma theophylline concentration on Day 7
in patients receiving cimetidine was significantly higher than on Days2 or12 (P < 0.05). The average increase in the
Cirnetidine
ReNt[dine
~xxxX-x-X~
15
Theophylline Dosage Doses of theophylline in b o t h groups r a n g e d f r o m 550 m g to 1.0 g. d -1 in divided doses. T h e u p p e r therapeutic limit of plasma theophylline was taken as 20 rag. 1 1.
K
101
E
14 p
Effect of cimetidine and ranitidine on plasma theophylline in patients with chronic obstructive airways disease treated with theophylline and corticosteroids W. B o e h n i n g Internal Medicine Clinic, Bad Lippspringe, Federal Republic of Germany
Summary. Thirty adults with chronic obstructive airways disease, who were stabilised on theophylline and corticosteroids, took part in a single blind study of the effects of cimetidine and ranitidine on plasma theophylline concentrations. The patients were randomised to receive either 150 mg ranitidine b.d. or 400 mg cimetidine b.d. for one week and serial plasma theophylline m e a s u r e m e n t s were made over a 12-hour period on two consecutive days before, during and after t r e a t m e n t with the H2-antagonist. There was a significant increase in plasma theophylline during treatment with cimetidine; two patients had levels > 20 mg. 1-1. The average increase in the theophylline concentration due to cimetidine was 32%. T h e r e was no significant change in plasma theophylline during ranitidine administration. No adverse effect occurred in any patient during the study. Key words: theophylline, ranitidine, cimetidine; obstructive lung diseases, drug interaction, plasma levels
Cimetidine interferes with the metabolism of the bronchodilator, theophylline, in man by interaction with the cytochrome P450 and P448 enzyme systems in hepatic microsomes (Jonkman and Upton, 1984; Dal Negro et al., 1984; Powell et al., 1984; Ferrari et al., 1984). As theophylline has only a narrow therapeutic plasma range (10-20 mg. 1-~), beyond which toxicity may appear, any drug interaction m a y have serious implications. Ranitidine has been shown not to interfere with theophylline metabolism in volunteers and in patients (Ruff, 1982; Powell et al., 1984; Ferrari et al., 1984; Dal Negro et al., 1984), but there are unconfirmed case reports of an interaction in chronically ill patients (Fernandez and Melewicz, 1984; G a r d n e r and Sikorski, 1984; R o y et al., 1988). The present study has examined the effect of treatment with cimetidine or ranitidine on steady state plasma theophylline concentrations in patients with chronic obstructive airways disease who were also receiving corticosteroids.
Material and methods Patients Hospital in-patients, aged 18-80 y, with severe chronic obstructive airways disease, who had been stabilised on theophylline and corticosteroids, were recruited for the study. Such patients normally also receive an H2-antagonist as prophylaxis against steroid-induced peptic ulceration. Patients were asked for their consent to participation in the study, even though the procedure formed part of the normal therapeutic investigative regimen. Excluded from the study were pregnant women and breast-feeding mothers, those with coincident renal, hepatic or other serious systemic disease, and those already established on H2-antagonists. Also excluded were smokers and those with intercurrent infection receiving tetracycline, erythromycin or aminoglycoside antibiotics, since those drugs are known to influence plasma theophylline concentrations (Jonkman and Upton, 1984).
Design A single-blind parallel group study was undertaken, in which patients were randomised to receive either ranitidine, or cimetidine. Plasma theophylline levels were estimated by staff not connected with the study, who were unaware of which treatment patients were receiving.
Materials Patients received a slow-release theophylline preparation, either Bronchoretard (Klinge) or PulmiDur forte (Astra), in an individually tailored dosage, which was kept constant throughout the study. All patients were receiving corticosteroids in individually tailored doses (29 on methylprednisolone and one on triamcinolone). Each of them received either ranitidine tablets, 150 mg b. d. or cimetidine tablets 400 mg b. d., for seven days.
Clinical Procedure Patients stabilised on theophylline and corticosteroid therapy were randomised to one of the two treatment groups, ranitidine or cometidine, by means of a predetermined code. Blood samples were taken before the study for routine haematological and biochemical screening.
W. Boehning: Cimetidine, ranitidine and theophylline kinetics
44 In addition plasma theophylline in each patient was estimated at the following times: (a) at 08.00 and 20.00 h immediately before dosing with theophylline (b) between doses of theophylline at 10.00,12.00 and 16.00 h. Patients receiving theophylline tds. took an additional dose at 12.30 h. Plasma theophylline was measured on two consecutive days, Study Days 1 and 2, before an H2-antagonist was given, again on Days 7 and 9 during H2-antagonist therapy, and finally on Days 12 and 14, after the H2-antagonist has been withdrawn. Ranitidine or cimetidine were given for one week from Study Days 3 to 9. Any clinical adverse events during the study were recorded in detail together with the treatment and outcome.
Laboratory procedures Plasma theophylline levels were determined in centrifuged, frozen samples using one calibration curve, using enzyme immuno-test kit (Emit-Test; Syva Corp, Darmstadt, Germany). The lower limit of detection was 0.5 mg. 1-1, with a variability of less than 1% on repeated determinations. Neither ranitidine nor cimetidine interfered with the test assay. The procedure is described by Gushaw et al. (1977).
Statistical Analysis Individual plasma theophylline concentrations within patients were compared using Student's t-test for paired data. Mean plasma theophylline concentrations on Days 2 and 12 were compared with those on Days 7 and 9. Mean plasma concentrations on Days 2 and 14 were also compared. The Wilcoxon rank sum test was used to compare all time points during Days 7 and 9 with those on Day 2.
Results
Patients' Thirty patients, 15 in each t r e a t m e n t group, t o o k part in the study. Details of sex, age and additional medication appear in Tables 1 and 2. The sex ratio differed in the two groups, there being m o r e females in the ranitidine group. Patients in the later group on average were also slightly older. However, those factors are unlikely to have a bearing on the results, as hepatic and renal function, as shown by laboratory biochemical data, were c o m p a r a b l e in the two t r e a t m e n t groups.
Table 1. Details of the Patients n M:F Mean age y range
Ranitidine
Cimetidine
15 5:10 55.1 42-67
15 11:4 62.3 47-74
Table 2. Additional medication (other than theophylline and corticosteroids)
Ranitidine group Patient no.
Medication
10 12 13 15 17 21 26 30
Budesonide Terbutaline, Dytide Isosorbide dinitrate, budesonide Bromazepam Digoxin, mianserin, Dytide, nifedipine Terbutaline, calcium Salbutamol Salbutamol; amoxycillin (during ranitidine)
Cimetidine group 1 6 7 8 11 14 16 18 19 22 24 27 29
Digoxin, Dytide Dytide, promethazine Budesonide Moduretic, oxazepam Amoxycillin (post-cimetidine) Budesonide Digoxin, terbutaline, bromazepam Isosorbide dinitrate Mianserin, abroxol Isosorbide dinitrate Digoxin, thiazide Ambroxol, isoniazid Digoxin, terbutaline, Dytide, glibenclamide
T h e r e was no significant difference b e t w e e n plasma theophylline concentrations in the pre- and post-cimetidine periods (Days 2 and 14). T h e mean plasma theophylline concentration on Day 7
in patients receiving cimetidine was significantly higher than on Days2 or12 (P < 0.05). The average increase in the
Cirnetidine
ReNt[dine
~xxxX-x-X~
15
Theophylline Dosage Doses of theophylline in b o t h groups r a n g e d f r o m 550 m g to 1.0 g. d -1 in divided doses. T h e u p p e r therapeutic limit of plasma theophylline was taken as 20 rag. 1 1.
K
101
E
14 p
