Therapeutic consequences of drug interactions with theophylline pharmacokinetics

doi:10.1016/0091-6749(86)90054-0

Journal of Allergy and Clinical Immunology

Volume 78, Issue 4, Part 2, October 1986, Pages 736-742

https://doi.org/10.1016/0091-6749(86)90054-0 Get rights and content

Abstract

Elimination of theophylline from the body occurs mainly (approximately 90%) by biotransformation, followed by excretion of the metabolites. Consequently, drugs affecting microsomal enzyme systems in the liver may alter the elimination of theophylline. Since theophylline has a rather narrow therapeutic window, dose adjustment might be necessary. Of the sympathomimetics, isoproterenol reduces theophylline clearance by 25%, but metaproterenol and terbutaline do not. Of the antibiotics, erythromycin and troleandomycin decrease theophylline clearance by 25% and 50%, respectively. No effect was observed with tetracycline, doxycycline, amoxicillin, cefaclor, and co-trimoxazole. On the other hand, rifampin (antituberculotic agent) increases theophylline clearance by 30%. Corticosteroids (hydrocortisone, methylprednisolone, and prednisone) do not affect theophylline kinetics. Influenza vaccination also has no influence. The antiulcerative agent (H₂ antagonist) cimetidine decreases theophylline clearance by 30%, but the agent ranitidine does not have any effect. Oral contraceptives may decrease theophylline elimination by 30%. Barbiturates and phenytoin may enhance theophylline clearance substantially (up to 75%). If an interaction is expected, careful monitoring of theophylline plasma concentrations is required to optimize the dose.

References (100)

MP Hemstreet et al.
Effect of intravenous isoproterenol on theophylline kinetics
J Allergy Clin Immunol
(1982)
JHG Jonkman et al.
The theophylline-erythromycin interaction
Chest
(1983)
CF La Force et al.
Effect of erythromycin on theophylline clearance in asthmatic children
J Pediatr
(1981)
CF La Force et al.
Effect of erythromycin base on theophylline pharmacokinetics in asthmatic children
J Allergy Clin Immunol
(1983)
RA Prince et al.
Effect of erythromycin on theophylline kinetics
J Allergy Clin Immunol
(1981)
MS Maddux et al.
The effect of erythromycin on theophylline pharmacokinetics at steady state
Chest
(1982)
M Weinberger et al.
Inhibition of theophylline clearance by troleandomycin
J Allergy Clin Immunol
(1977)
JHG Jonkman et al.
Lack of influence of cotrimoxazole on theophylline pharmacokinetics
J Pharm Sci
(1985)
WJ Jusko et al.
Factors affecting theophylline clearance: Age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates and ethanol
J Pharm Sci
(1979)
KC Chang et al.
Altered theophylline pharmacokinetics during acute respiratory viral illness
Lancet
(1978)

S Walker et al.

Serum theophylline levels after influenza vaccination

Can Med Assoc J

(1981)

L Shargel et al.

Effect of antacids on bioavailability of theophylline from rapid and time-release drug products

J Pharm Sci

(1981)

RK Roberts et al.

Cimetidine impairs the elimination of theophylline and antipyrine

Gastroenterology

(1981)

RL Lalonde et al.

The effects of cimetidine on theophylline pharmacokinetics at steady state

Chest

(1983)

AW Green et al.

Cimetidinemethylprednisolone-theophylline metabolic interaction

Am J Med

(1984)

RA Landay et al.

Effect of phenobarbital on theophylline disposition

J Allergy Clin Immunol

(1978)

KA Conrad et al.

Orciprenaline does not alter theophylline elimination

Br J Clin Pharmacol

(1981)

P Godard et al.

Influence d'un bêtamimétique sur les paramètres pharmacocinetiques de la theophylline

Rev Fr Allergol Immunol Clin

(1981)

Y Danziger et al.

Reduction of serum theophylline levels by terbutaline in children with asthma

Clin Pharmacol Ther

(1985)

Jonkman JHG, Van der Boon WJV, Grasmeyer G. No change in theophylline pharmacokinetics during terbutaline therapy. (In...

P O'Rourke et al.

Effect of isoproterenol on measured theophylline levels

Crit Care Med

(1984)

CF La Force et al.

Effect of erythromycin on theophylline clearance in asthmatics

J Allergy Clin Immunol

(1981)

BJM Zarowitz et al.

Effect of erythromycin base on theophylline kinetics

Clin Pharmacol Ther

(1981)

KW Renton et al.

Depression of theophylline elimination by erythromycin

Clin Pharmacol Ther

(1981)

A Iliopoulou et al.

Pharmacokinetic interaction between theophylline and erythromycin

Br J Clin Pharmacol

(1982)

BM Stults et al.

Effect of erythromycin stearate on serum theophylline concentrations in patients with chronic obstructive lung disease

South Med J

(1983)

HJ Pfeifer et al.

Effects of three antibiotics on theophylline kinetics

Clin Pharmacol Ther

(1979)

SJ Kelly et al.

No effect of erythromycin on plasma theophylline levels

Clin Res

(1981)

S Melethil et al.

Steady state urinary excretion of theophylline and its metabolites in the presence of erythromycin

Res Commun Chem Pathol Pharmacol

(1982)

DC May et al.

The effects of erythromycin on theophylline elimination in normal males

J Clin Pharmacol

(1982)

G Reisz et al.

The effect of erythromycin on theophylline pharmacokinetics in chronic bronchitis

Am Rev Respir Dis

(1983)

JL Brazier et al.

Retard d'elimination de la théophylline dû à la troleandomycine. Absence d'effet de la josamycine

Therapie

(1980)

J Lavarenne et al.

Influence d'un nouveau macrolide, la midécamycine, sur les taux sanguins de théophylline

Therapie

(1981)

JW Mathis et al.

Effect of tetracycline hydrochloride on theophylline kinetics

Clin Pharm

(1982)

JHG Jonkman et al.

Lack of effect of amoxicillin on theophylline pharmacokinetics

Br J Clin Pharmacol

(1985)

JHG Jonkman et al.

No effect of cefaclor on theophylline pharmacokinetics

Eur J Respir Dis

(1985)

JHG Jonkman et al.

No influence of doxycycline on theophylline pharmacokinetics

Ther Drug Monit

(1985)

JS Seggev et al.

Doxycycline does not affect theophylline levels

Ann Allergy

(1985)

AR Hauser et al.

The effect of rifampin on theophylline disposition

Clin Pharmacol Ther

(1983)

AB Straughn et al.

Effect of rifampin on theophylline disposition

Ther Drug Monit

(1984)

EG Boyce et al.

The effect of rifampin on theophylline kinetics

Clin Pharmacol Ther

(1985)

PR Powell-Jackson et al.

Effect of rifampicin administration on theophylline pharmacokinetics in man

Thorax

(1984)

RA Robson et al.

Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways

Br J Clin Pharmacol

(1984)

N Buchanan et al.

Asthma—a possible interaction between hydrocortisone and theophylline

S Afr Med J

(1979)

DC Leavengood et al.

The effect of corticosteroids on theophylline metabolism

Ann Allergy

(1983)

H Albin et al.

Pharmacocinétique de la theophylline par voie orale chez des malades asthmatiques sous corticothérapie au long cours

Therapie

(1983)

JL Anderson et al.

Potential pharmacokinetic interaction between theophylline and prednisone

Clin Pharm

(1984)

MJ Kraemer et al.

Altered theophylline clearance during an influenza B outbreak

Pediatrics

(1982)

KW Renton et al.

Decreased elimination of theophylline after influenza vaccination

Can Med Assoc J

(1980)

RS Goldstein et al.

Decreased elimination of theophylline after influenza vaccination

Can Med Assoc J

(1982)

Cited by (40)

Compatibility of medication with PRISCUS criteria and identification of drug interactions in a large cohort of patients with COPD
2018, Pulmonary Pharmacology and Therapeutics
Patients with COPD are often of advanced age and have a high number of medications due to their lung disease and comorbidities. Thus they are at risk for unwanted effects from drugs, either due to age or due to interactions between drugs. These issues are not clarified. We therefore assessed the number of medications and potential adverse effects in a large cohort of patients with COPD.
The analysis was performed in 2741 patients of the German COPD cohort COSYCONET, using baseline data (visit 1) and follow-up data after about 1.5 years (visit 3). Spirometric GOLD grades 1–4 were found in 8/35/32/9% of patients and GOLD groups ABCD in 7/25/4/48% of patients, while the remaining patients (n = 450, 16.4%) could not be classified according to GOLD criteria. The compatibility of medication with age was evaluated via the PRISCUS list, drug interactions via the AiD clinic system, whereby only drug combinations occurring in at least 10 patients were considered (nine unwanted interactions, one wanted interaction).
The median numbers of medications were 5 or more in all patient categories, among them 3 or more non-respiratory medications. In the total population there were 153 patients (10.2%) aged ≥65 years who had any medication of the PRISCUS list with intermediate or low risk. Serious adverse combinations of drugs according to AiD occurred in 114 patients (4.2%), while the number of unwanted but only potentially clinically relevant combinations was 175 (6.4%). The number of wanted combinations was 219 (8.0%). These numbers did not markedly change when restricting the analysis to patients of GOLD grades 1–4. Moreover, the results were similar for visit 1 and visit 3.
We conclude that in a large cohort of COPD patients about 10% of patients aged at least 65 years had medications that could interfere with their age and that the proportions of patients with either unwanted or wanted drug interactions were both in the range of 8–10%. These results suggest that problems arising from the high number of medications were not very frequent in the COPD cohort analysed.
Oral contraceptives
2008, Psychosomatics
Citation Excerpt :
OCs decrease the clearance of caffeine and theophylline, wellknown substrates of 1A2.57–61 Because a 30% decrease in theophylline clearance occurs with OC use,62 clinicians should reduce theophylline doses. The side-chain oxidation of propranolol is catalyzed by 1A2, and this process is inhibited by OCs.63,64
Nearly 50 years ago, the introduction of Enovid^© (norethynodrel 10 μg and mestranol 150 μg), which provided convenient and reliable contraception, revolutionized birth control. Reports of interactions between oral contraceptives (OCs) and other drugs began to trickle into the literature. At first, these drug interactions appeared to be random and unrelated. Increased understanding of P450 enzymes and phase II reactions of sulfation and glucuronidation has permitted preliminary categorization and assessment of the clinical relevance of these drug interactions
PDE4 inhibitors in COPD - A more selective approach to treatment
2004, Respiratory Medicine
Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic index compared with the weak, non-selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by poor efficacy and an unfavourable safety and tolerability profile, the selective PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in improving lung function, decreasing the rate of exacerbations and improving quality of life, with proven anti-inflammatory effects in patients with COPD. Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications. In contrast, the selective PDE4 inhibitors are convenient medications for both patient and physician alike. Hence these agents represent a therapeutic advance in the treatment of COPD, due to their novel mechanism of action and potent anti-inflammatory effects, coupled with a good safety and tolerability profile.
Increased theophylline metabolism in the menstrual phase of healthy women
1997, Journal of Allergy and Clinical Immunology
Background: We previously reported on a Japanese woman with premenstrual asthma whose serum theophylline concentration was lower before the onset of her menstrual period. We evaluated the clearance of theophylline in each phase of her menstrual cycle and found an increase in clearance in the premenstrual and menstrual phases. Objective: This study was designed to investigate whether changes in theophylline clearance may occur with the menstrual cycle in nonasthmatic women. Methods: Aminophylline, 250 mg, was infused intravenously for 45 minutes, and the clearance of theophylline was calculated in seven healthy, ovulatory women on days 1 or 2, 10, and 20 or 25 of the menstrual cycle. The serum concentration of theophylline was determined with an enzyme immunoassay (homogeneous). Results: Theophylline clearance was significantly higher and its half-life was significantly shorter in the menstrual phase than in the follicular phase. Conclusion: The metabolism of theophylline, and consequently, its clearance were increased in healthy women around the onset of menses. Clinicians must therefore consider the menstrual variation in theophylline metabolism when prescribing this drug to female patients. (J Allergy Clin Immunol 1997;100:39-43.)
Threshold level for theophylline in doping analysis
1996, Journal of Chromatography B: Biomedical Applications
HPLC in the reversed-phase mode is used to assay methylxanthines including theobromine, paraxanthine, theophylline and caffeine in urine. The calibration graphs show good linearity in the concentration range 0–10 μg/ml. The limit for accurate quantitation of theophylline was 0.25 μg/ml. Between 6 and 20% of the parent drug is recovered in urine (0–12 h) after the oral administration of sustained release preparations containing 150 and 250 mg theophylline to four volunteers. Theophylline levels above 0.25 μg/ml were found in 1539 out of 3885 urine samples collected from athletes during unannounced doping control in Flanders. Statistical evaluation of the results gives a far outside value [75th percentile + (3× interquartile range)] of 2.25 μg/ml. The ratio theophylline paraxanthine (TP/PX) as an indicator for the non-dietary intake of theophylline seems to be more reliable. The far outside ratio was 0.20. To ensure with the greatest possible degree of certainty that no false-positive result is reported, decision limits of 5 μg/ml and 0.50, for theophylline and the ratio TP/PX respectively, are proposed.
Aminophylline in the emergency department: Maximizing safety and efficacy
1991, Chest
An experimental technique designed to predict theophylline doses needed to attain therapeutic theophylline concentrations in 43 emergency department (ED) patients was compared with a standard conventional regimen in 46 ED patients. The experimental protocol utilized a computer-assisted dosage prediction program that incorporated baseline theophylline concentration rapidly obtained using a bedside assay. The standard protocol used conventional loading and infusion rates, as well as an estimate of time of last theophylline dose based on patient history. Plasma theophylline concentrations, estimated 1 and 6 hours after commencement of aminophylline therapy in each regimen, were compared. The experimental protocol was equally rapid but much more accurate in achieving targeted theophylline concentrations. Experimental dosage prediction was associated with a higher proportion of theophylline concentrations in the therapeutic range at 1 (81 percent vs 26 percent; p<0.001) and 6 hours (91 percent vs 37 percent; p<0.001). There was a trend toward fewer toxic concentrations recorded at 1 (0 percent vs 7 percent; p=0.27) and 6 hours (0 percent vs 10 percent; p=0.08). This protocol, which was performed quickly and without difficulty by residents in a busy hospital ED, offers an opportunity to improve the efficacy and decrease the toxicity of theophylline use in asthma emergencies.

View all citing articles on Scopus

View full text

Therapeutic consequences of drug interactions with theophylline pharmacokinetics

Abstract

J Allergy Clin Immunol

Chest

J Pediatr

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

J Pharm Sci

J Pharm Sci

Lancet

Can Med Assoc J

J Pharm Sci

Gastroenterology

Chest

Am J Med

J Allergy Clin Immunol

Orciprenaline does not alter theophylline elimination

Br J Clin Pharmacol

Influence d'un bêtamimétique sur les paramètres pharmacocinetiques de la theophylline

Rev Fr Allergol Immunol Clin

Reduction of serum theophylline levels by terbutaline in children with asthma

Clin Pharmacol Ther

Effect of isoproterenol on measured theophylline levels

Crit Care Med

Effect of erythromycin on theophylline clearance in asthmatics

J Allergy Clin Immunol

Effect of erythromycin base on theophylline kinetics

Clin Pharmacol Ther

Depression of theophylline elimination by erythromycin

Clin Pharmacol Ther

Pharmacokinetic interaction between theophylline and erythromycin

Br J Clin Pharmacol

Effect of erythromycin stearate on serum theophylline concentrations in patients with chronic obstructive lung disease

South Med J

Effects of three antibiotics on theophylline kinetics

Clin Pharmacol Ther

No effect of erythromycin on plasma theophylline levels

Clin Res

Steady state urinary excretion of theophylline and its metabolites in the presence of erythromycin

Res Commun Chem Pathol Pharmacol

The effects of erythromycin on theophylline elimination in normal males

J Clin Pharmacol

The effect of erythromycin on theophylline pharmacokinetics in chronic bronchitis

Am Rev Respir Dis

Retard d'elimination de la théophylline dû à la troleandomycine. Absence d'effet de la josamycine

Therapie

Influence d'un nouveau macrolide, la midécamycine, sur les taux sanguins de théophylline

Therapie

Effect of tetracycline hydrochloride on theophylline kinetics

Clin Pharm

Lack of effect of amoxicillin on theophylline pharmacokinetics

Br J Clin Pharmacol

No effect of cefaclor on theophylline pharmacokinetics

Eur J Respir Dis

No influence of doxycycline on theophylline pharmacokinetics

Ther Drug Monit

Doxycycline does not affect theophylline levels

Ann Allergy

The effect of rifampin on theophylline disposition

Clin Pharmacol Ther

Effect of rifampin on theophylline disposition

Ther Drug Monit

The effect of rifampin on theophylline kinetics

Clin Pharmacol Ther

Effect of rifampicin administration on theophylline pharmacokinetics in man

Thorax

Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways

Br J Clin Pharmacol

Asthma—a possible interaction between hydrocortisone and theophylline

S Afr Med J

The effect of corticosteroids on theophylline metabolism

Ann Allergy

Pharmacocinétique de la theophylline par voie orale chez des malades asthmatiques sous corticothérapie au long cours

Therapie

Potential pharmacokinetic interaction between theophylline and prednisone

Clin Pharm

Altered theophylline clearance during an influenza B outbreak

Pediatrics