Fundam Clin Pharmacol(1991) 5, 341-345 0 Elsevier, Paris

34 1

Short Communication

Nifedipine alters serum theophylline levels in asthmatic patients with hypertension E Yilmaz, A Canberk, L Eroglu* Department of Pharmacology, Istanbul Medical Faculty, University of Istanbul, capa, Istanbul, Turkey (Received 18 December 1989; accepted 18 December 1990)

Summary - The effect of nifedipine on serum theophylline levels in 13 female hypertensive patients having asthma on theophylline therapy has been investigated. Administration of a slow release theophylline product in a dose of 200 mg bidaily for 15 days provided a steady-state trough serum theophylline concentration (1 1.2 f 2.7 pglml). After this period, 10 mg bidaily nifedipine was added to therapy and trough serum theophylline levels, pulmonary function tests and blood pressure measurements have been performed following 15 and 45 days of simultaneous use of theophylline and nifedipine. No change has been observed in serum theophylline level after 15 days of simultaneous use, however after 45 days, serum theophylline level was significantly lower (7.3 1 pg/ml). There were no changes in clinical responsiveness of either of these drugs.

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nifedipine I serum theophylline I blood pressure I lung function tests

Introduction Theophylline is one of the most effective drugs for therapeutic approach to patients with asthma or with other chronic bronchial obstructive diseases. However, several drugs influence theophylline pharmacokinetics (Bukowskyj et al, 1984 ; Jusko et al, 1979) and this aspect is important in view of the narrow therapeutic range of t heoph ylline. On the other hand, calcium channel blockers are being used increasingly for both hypertension and angina and they are recommended alternatives for the treatment of these diseases in patients with airway obstruction in whom P-blockers are contraindicated. In addition, calcium channel blockers are claimed to reduce airway reactivity to a variety of stimuli (Barnes, 1985; Barnes et al, 1981 ; Massey and Hendeles, 1987). We have therefore evaluated the effect of nifedipine both on serum levels and the effectiveness of theophylline in hypertensive patients having asthma on theophylline therapy.

'Correspondence and reprints

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E Yilmaz er a/

Materials and Methods Subjects This study has been performed in 13 nonsmoker female asthmatic and borderline isolated syotolic hypertensive (Schroeder, 1989) patients with a mean age of 43.7 years (range 32-55), mean weight of 71.8 kg (range 59.2-84.4) and with mean systolic and diastolic arterial blood pres4.6 mmHg (range 94.6-85.4) respecsure 148.8 f 14.0 mmHg (range 13.8-162.8) and 90.0 tively. Alcohol and xantine contained in food or beverage were prohibited 48 h before and during the study. N o medication was taken by the subjects from 1 week before the study until its completion. Each subject gave written informed consent. All patients had normal hepatic and renal functions.

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Protocols The study was designed as double blind. Pulmonary function tests (Forced expiratory volume in one second : FEV, ; peak expiratory flow rate: PEFR) were measured by means of an apparatus (Mijinhard-Vicatest 4) and mean systolic and diastolic arterial blood pressures were estimated. Since then, each patient received one slow release theophylline capsule containing 200 mg anhydrous theophylline (Talotren, Sandoz) and blood samples for the determination of serum theophylline were taken 2, 4, 24 h after dosing. After ensuring serum theophylline concentration of over 8 pg/ml, the study began. Each patient received two theophylline capsules and two placebo tablets on a day at '12 h intervals (at 8.00 and 20.00 h before meals with half a glass of water). This procedure lasted 15 days. At the end of this period, just before the morning dose, blood sample was taken and lung function and arterial blood pressure were estimated at the same time. After having morning theophylline dose, volunteers started taking nifedipine tablet (Nidilat, DIF) at a dose of 10 mg bidajly (Just after theophylline capsule each time) and serum theophylline levels, pulmonary function tests and arterial blood pressure measurements have been performed following 15 and 45 days of simultaneous use of theophylline and nifedipine. A nalysis

Serum theophylline level was estimated by means of a spectrophotometric method (Jenne et at, 1972). Student's t-test was used for statistical comparisons. The result were given as mean f sd.

Results

Serum theophylline levels As seen in table I, the mean serum theophylline level 4 h after a single 200 mg dose of theophylline was 8.7 f 2.8 pg/ml and the steady-state trough serum theophylline concentration was 11.2 & 2.7 pg/rnl after 15 days administration of a slow release

Effect of nifedipine on serum theophylline levels

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theophylline preparation in a dose of 200 mg bidaily. Adding of 10 mg bidaily nifedipine of the patierlts therapy, no change has been observed in serum trough theophylline concentration after 15 days of simultaneous use of both drugs, however, after 45 days, serum trough theophylline concentration was significantly lower (7.3 +. 1 pg/ml).

Pulmonary Function Tests Forced expiratory volume in one second (FEV,) and peak expiratory flow rate (PEFR) were significantly increased in response to either acute or 15 days' theophylline treatment. It seemed that adding nifedipine to the therapy did not cause any significant alteration in theophylline-induced increase of pulmonary functions (table I).

The Arterial Blood Pressure The mean systolic and diastolic arterial blood pressures were not changed during theophylline therapy alone. However, after adding nifedipine to the therapy the mean systolic and diastolic arterial blood pressures were significantly lower and this decrease lasted in the course of the experiment (table I).

Table I. Mean forced expiratory volume in one second (FEV,), mean peak expiratory flow rate (PEFR) and mean systolic and diastolic arterial blood pressure (BP) values and serum theophylline levels ( + sd) in patients treated with theophylline and nifedipine.

5P Treatment

Bf diastolic mm Hg

PEFR

Baseline

1.6 i 0.5

2.9 i 1.4

148.8 k 14.0

90

Theophylline (4th h)

1.9 i 0.5"

5.2 k 1.8**

148.8 ? 14.1

90.4 i 4.3

8.7 k 2.8

Theophylline (15th day)

2

5.8 t 1.8***

150.0 k 13.2

91.5 t 3.7

11.2 f 2.7

132.3 i 13.7*

77.3 i 4.8'

10.0 ? 5.4

5.7 t 1.6*** 125.7 k 15.5*

70.8 i 10.7'

11.4 T 3.7

Nifedipine (4th h, theophylline treated patients) Theophylline (15th day)

+ nifedipine

Theophylline (45th day)

+

k 0.5**

1.4 i 0.5** 5.5 i 1.5***

1.9 i 0.4**

nifedipine 2.0 f 0.5** 5.7 k 1.4***

Systolic mm Hg

Serum theophylline level I.cg/ml

FEV,lL'

126.9 k 14.2*

f 4.6

71.9 f 16.8'

-

7.3 i 2.1a,b

* P < 0.05, * * P 0.01, *** f < 0.001 versus baseline. ap 0.001 versus theophylline 15th day. b, 0.001 versus theophylline + nifedipine 15th day.

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Discussion There has been a small number of studies related to nifedipine and theophylline interactions and most of them are conflicting. Data about nifedipine-induced increase in serum theophylline concentration- are mainly based on inadequatly documented case reports (Harrod, 1987;Parrillo et al, 1984). Lack of significant change in half life of single dose of theophylline in one week nifedipine pretreated healthy volunteers has also been demonstrated (Sirmans et al, 1988). On the.other hand, Smith et al(1987) have reported two weeks' nifedipine treatment induced a decrease in serum theophylline concentration. This result is partly consistent with the present study. However, their protocol has been slightly different from ours as being placebo controlled cross over one. In our study, 15 days' administration of nifedipine to the borderline isolated systolic hypertensive and asthmatic patients caused no change in trough serum theophylline concentration while a significant decrease was observed after a 45 day-treatment. Obviously, this decrease in trough serum theophylline level would 'have happened at any time between 15th and 45th days of nifedipine treatment. A number of possible mechanisms for the fall in theophy1line:xoncentration during nifedipine administration can be proposed ; theophylline clearance might be accelerated by the increasing effect of nifedipine on liver blood flow (Seely, 1984).This is, however, unlikely since its clearance is dependent on the activity of hepatic enzymes rather than on hepatic blood flow (Jack, 1985).Theophylline;indeed, is metabolized by microsomal oxidative enzymes. However, nifedipine has been found to have *noeffect on antipyrine clearance which is an in vivo indicator of hepatic oxidative metabolism (Bauer et dl, 1986). Alternatively, nifedipine might decrease theophylline absorption. However, accord'ing to the study of Jackson et al(1986), serum theophylline concentrations after.an .. ;intravenous infusion of lysine theophylline were significantly lower in long term oral nifedipine treated healthy subjects.'Theyproposed that the fall in the serum theophylline concentration, might be due to nifedipine, which induced an increase in.the:mean volume of distribution of theophylline. Nevertheless this ,proposal seems to be ifar Lto:explain our finding. In our:study, the.interaction between theophylline,and nifedipine,occured;during,steady stateshronic oral dosing of'both

Nifedipine alters serum theophylline levels in asthmatic patients with hypertension.

The effect of nifedipine on serum theophylline levels in 13 female hypertensive patients having asthma on theophylline therapy has been investigated. ...
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