Therapeutic consequences of drug

interactions with theophylline

pharmacokinetics

Jan H. G. Jonkman, Ph.D. Assen and Groningen, The Netherlands

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 e!imination 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, etythromycin 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, rtfampin
(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 (H, 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. (J ALLERGY CLINIMMUNOL
1986:78:736-42.)

The use of theophylline as a bronchodilator in the
treatment of chronic airway obstruction has greatly
increased since the late 1970s. At that time, sustained-
release preparations to improve therapy and to en-
hance patient compliance became available, and better
methods for measuring theophylline plasma concen-
trations allowed optimum individual dosing.
Because of both the drug’s narrow therapeutic win:
dow (approximately 7.5 to 20 mg * L-‘) and its ex-
tensive biotransformation in the liver (90%), modest
changes in the absorption or elimination of theoph-
ylline due to coadministered drugs may result in sub-
therapeutic or toxic concentrations in plasma.
These drug-to-drug interactions may be of a bio-
pharmaceutical or of a pharrnacokinetic nature. Bio-
pharmaceutical drug interactions in most cases are due
to interferences with the dissolution process of the-
ophylline in the gastrointestinal tract. in many cases
such interactions are related to the additives used in
From the State University, Department of Pharmaceutical and An-
alytical Chemistry, Groningen, The Netherlands.
Reprint requests: Dr. Jan H. G. Jonkman, Department of Bio-
pharmaceutics and Clinical Pharmacokinetics, Pharma Bio-Re-
search Int’l b.v., P.O. Box 147, NL 9400 AC Assen, The Neth-
erlands.
the manufacturing process of the dosage form and not
to the drug itself.
Pharmacokinetic interactions with theophylline
may be caused by other drugs influencing the liver
function (e.g., microsomal enzyme systems and he-
patic uptake) or, to a lesser extent, the renal elimi-
nation route. Such interactions may be unavoidable
in a given combination of drugs. They will require
dosage adjustment of theophylline or prescription of
an alternative drug from the same therapeutic group.
This article reviews the pharmacokinetic interac-
tions with theophylline that have been recently re-
ported. Special attention is paid to their clinical rel-
evance.
SYMPATHOMIMETICS
A pharmacokinetic interaction between sympatho-
mimetic drugs (P-agonist bronchodilators) is of great
importance since these drugs are frequently used con-
comitantly with theophylline by patients with asthma.
Unfortunately, the literature on this subject is scarce.
A possible interaction of metaproterenol (orciprena-
line) was studied by Conrad and Woodworth.’ The
clearance of theophylline was not significantly altered
by a 3-day course of 60 mg orciprenaline per day or
by inhalation of 1.95 mg four times a day. The du-

736
VOLUME 78
NUMBER 4, PART 2
ration of orciprenaline therapy, however, is considered
to be rather short.
A single dose of 0.5 mg terbutaline subcutaneously
did not influence theophylline kinetics in 14 patients,*
but such a study design does not give information on
a terbutaline-theophylline interaction during long-
term treatment. Danziger et a1.3found that a 14-day
course of orally administered terbutaline (0.075 mg .
kg ’ three times a day) decreased the mean predose
theophylline plasma concentration from 13.8 ? 4.0
mg . L-’ to 10.8 IL 3.6 mg . L-’ in 12 children with
asthma (7 to 11 years of age).
Jonkman et a1.4 studied the pharmacokinetics of
theophylline when the drug was given for 7 days with
or without oral doses of 15 mg terbutaline per day for
the same period, to 12 healthy subjects. No significant
changes could be found in any of the pharmacokinetic
parameters.
The data on isoproterenol (isoprenaline) suggest
that theophylline clearance is increased immediately
by intravenous administration of isoproterenol. Hem-
street et al.’ measured an increased clearance of about
20% and O’Rourke et a1.6 reported a 30% decrease
of theophylline plasma concentrations in 12 patients
in status asthmaticus during isoproterenol infusion.
These findings indicate that theophylline monitoring
is advisable during isoproterenol infusion.
ANTIBIOTICS
Antibiotics are frequently coadministered with the-
ophylline (e.g., during acute exacerbations of bron-
chitis and infections of the upper and lower respiratory
tract). Many antibiotics are metabolized in the liver
and may therefore stimulate or inhibit theophylline
clearance during periods of co-medication.
The macrolide antibiotic erythromycin has been ex-
tensively investigated. The literature on theophylline-
erythromycin interaction seems very contradictory. In
several papers a significant interaction was demon-
strated. whereas in others no changes in theophylline
clearance were found.
Critical evaluation of the literature,’ however, re-
veals that probably the duration of the co-medication
and the peak of the plasma erythromycin concentra-
tions are the factors that determine whether or not an
interaction will occur. A 9% to 40% decrease in the-
ophylline clearance (and a 15% to 60% increase in
half-life) was observed in studies in which erythro-
mycin was administered for 6 days or more.“-‘5
On the contrary, no significant interaction was
observed when the drug was given for 5 days or
less.ihm” In clinical. practice, administering 7-day to
IO-day courses of erythromycin, an approximate 25%
Drug interactions with theophylline pharmacokinetics 737
reduction in the theophylline dose within 6 days after
the start of the course may be desirable.
Another macrolide antibiotic troleandomycin given
in a IO-clay course, has been reported to reduce the-
ophylline clearance at steady state by 50%.” Brazier
et a1.23and Lavarenne et a1.‘4 reported an increase (of
99% and 27%, respectively) in the half-life of the-
ophylline when both drugs were given concomitantly
in a single dose. As a result, a reduction of the the-
ophyllinc dose by 50% or more may be necessary
during co-medication with troleandomycin. The same
authors showed that josamycin and midecamycin had
no effect on theophylline kinetics.
Not all antibiotics influence theophylline pharma-
cokinetics. Mathis et al.*’ found no significant dif-
ference in pharmacokinetic parameters of theophylline
before and after a 7-day course of tetracycline.
In a comparable study design (sustained-release the-
ophylline preparation during 9 days with and without
antibiotics), no significant influence on theophylline
clearance was reported for the “second-generation”
cephalosporin ccfaclor, for amoxicillin, and for do-x-
ycycline. ‘h-28Seggev et a1.29also reported unchanged
steady-state theophylline plasma concentrations dur-
ing doxycycline co-medication. A 9-day course of co-
trimoxazole did not have an effect on single-dose the-
ophylline pharmacokinetics.“”
These results indicate that administration of cefa-
clor, amoxycillin, co-trimoxazole, doxycycline, and
tetracycline-all antibiotics that are frequently pre-
scribed for patients with asthma-does not necessitate
an adjustment in theophylline dosage.
Rifampin (rifampicin), an antituberculotic agent,
is a known inducer of cytochrome P-450 enzymes.
It increases the rate of metabolism of several drugs
(anticoagulants, oral contraceptives, digitoxin, quin-
idine, antipyrine). Recently it was reported that
rifampin increases theophylline clearance substan-
tially (25%, Hauser et a1.3’; 25%, Straughn et al.‘?
38%, Boyce et al.“; 45%, Powell-Jackson et al.‘“;
82%, Robson et a1.‘5). The last study revealed that
both demethylation and g-oxidation processes were
increased.
CORTICOSTEROIDS
Another group of drugs that is frequently included
in the drug therapy of patients with asthma comprises
the corticmosteroids.Unfortunately, almost no system-
atic studies have been conducted to determine their
possible pharmacokinetic interaction with theophyl-
line. Buchanan et a1.j6reported peak theophylline con-
centrations of 40 to 50 rng.L-’ in six patients in status
asthmaticus who were treated with high doses of hy-
738 Jonkman
drocortisorle, but decreased elimination might be due
to the acute illness.
Leavengood et al. ,37however, found no change in
clearance when healthy volunteers were treated with
two doses of’ 8 mg.kg-’ hydrocortisone.
in a similar study the authors found no change in
theophylline kinetics after two doses of methylpred-
nisolone, Albin et a1.38reported that theophylline
clearances in patients with asthma who were treated
for more than 3 years with methylprednisolone was
not different from the values in a control group. It
was also reported that one dose of prednisone did not
result in an interaction.39 In a retrospective survey of
pharmacokinetic, pathophysiologic, and historical
factors that could influence theophylline clearance,
Jusko et al.” reported that corticosteroids had no sig-
nificant effect.
Therefore, it is likely that no adjustment in the-
ophylline dosage is required during long-term cotreat-
ment with corticosteroids.
INFLUENZA VACCINATION
Influenza vaccination is generally recommended for
patients suffering from chronic pulmonary disease;
many of these patients may be undergoing long-term
theophylline therapy.
In 1978 it was demonstrated by Chang et a1.4’ that
acute respiratory viral illness increased theophylline
half-life by 108% 2 121% in six children. Kraemer
et al.J’ described symptoms of theophylline toxicity
due to reduced theophylline clearance in I1 children
during an influenza B outbreak. These findings stim-
ulated research on the effect of influenza vaccination
on theophylline pharmacokinetics.
Renton et al .43reported an increase of 85% to 2 19%
in steady-state theophylline concentrations in three
asthmatic patients within 12 to 24 hours after influenza
vaccinations. Two of the patients experienced serious
side effects.
The author found that in four healthy volunteers,
theophylline clearance was decreased by 51.9% i
14% after administration of influenza vaccinations.
Walker et al .4Jdescribed an increase in theophylline
serum concentration from 20 to 34 mg . L-‘. Since
then, however, no change in theophylline pharma-
cokinetics was reported by any investigator who stud-
ied this potential interaction. These studies were
performed with different vaccines, both in healthy
volunteers, and in asthmatic patients of several ages
(children, adults and elderly).45-5’ Since Renton et a1.43
had been using a nonspecific ultraviolet spectropho-
tometric method for measuring theophylline plasma
concentrations, we decided to conduct a study in
J. ALLERGY CLIN. IMMUNOL.
OCTOBER 1986
which the plasma samples before and after vaccination
were measured by the same method, and by a selective
high-performance liquid chromatography method, and
by means of the enzyme multiplied immunoassay
technique. We also reported no significant changes in
theophylline kinetics.52 These recent findings suggest
that no .:heophylline dose adjustment is necessitated
during influenza vaccination.
ANTACIDS
Many patients with asthma take antacids along with
theophylline to avoid some of its gastric irritation.
During the concomitant presence of both drugs in the
stomach, a biopharmaceutical interaction is possible
because theophylline is more soluble at higher pH
values.
Different effects may be noted with immediate, en-
teric-coated, or sustained-release products, with dif-
ferent salts, or with preparations with adjuvants
having different physicochemical properties.
Arnold et al.51 found that antacids can significantly
decrease the absorption rate of aminophylline (the-
ophyllint: ethylenediamine). The extent of absorption
and elimination rates was not affected. On the con-
trary, Reed et al.-54observed no effect on absorption
rate with such a preparation. Likewise, no effect was
seen when rapid-release (Slo-phyllin) tablets were in-
gested with antacids.“’ Antacids do not seem to affect
the biopharmaceutical properties of some sustained-
release preparations, such as Slo-Phyllin Gyrocaps
(William H. Rorer, Inc., Ft. Washington, Pa.) and
Theo-Dur (Key Pharmaceuticals, Inc., Miami,
Fla.).5“-‘s A slightly faster absorption rate was ob-
served with another sustained-release preparation
(Theolair S. R., Riker Laboratories Inc., Northridge,
Calif.). 5XIn general, the observed alterations do not
have a large clinical impact.
H, ANTAGONISTS
The HZ antagonist cimetidirze is known to inhibit
hepatic microsomal mixed-function oxidase metabo-
lism, and to decrease the clearance of many drugs
(e.g., warfarin, phenytoin, propranolol, diazepam and
chlordiazepoxide). Since it is frequently coadminis-
tered with theophylline in ulcer patients with airways
obstruction, a pharmacokinetic interaction is of clin-
ical importance. Jackson and co-workerssgh were the
first to report a significant (39%) decrease in theoph-
ylline clearance already after a 2-day cimetidine
course.
Many tc@herreports on this interaction have been
published; in most publications a 20% to 40% decrease
in theophylline clearance is given. The interaction
VOLUME 78
Drug interactions
NUMBER 4, PART 2
may result in toxic theophylline concentrations with
severe side effects (e.g., vomiting, seizures, death).
It is now obvious that the interaction occurs rather
rapidly6’ and reaches a maximum level after 2 to 3
days.”
The interaction is observed in children,@ (young)
adults,63. 6’-73and the elderly.74-77The extent of the
effect is not related to age.” It occurs both in healthy
subjects and asthma patients. Some authors66.72found
that the effect was more pronounced in smokers than
in nonsmokers, but others78 observed no difference.
In addition, the extent of the reduction in theophylline
clearance is independent of the cimetidine dose.“. ”
The exact mechanism of the interaction is not yet
revealed. Grygiel and others72found that the reduction
in theophylline clearance was largely due to a reduc-
tion in metabolic clearances by 3-demethylation and
I-demethylation, with no significant effect on clear-
ance by 8-oxidation (formation of methyluric acids).
A similar conclusion was drawn by Green et a1.79from
the results of a case report study. From these data it
is clear that a substantially higher steady-state the-
ophylline plasma concentration may occur during co-
medication with cimetidine. A theophylline dose re-
duction by 30% or more may be required.
A newer II2 receptor antagonist, ranitidine, is struc-
turally different from cimetidine. Ruff” found the-
ophylline clearance was not affected by treatment with
ranitidine. In two studie@‘, ” the effect of cimetidine
and ranitidine on the pharmacokinetics of theophylline
was compared in the same panel of subjects. Cimet-
idine changed theophylline clearance substantially
(see above), but ranitidine did not have a significant
effect. Dal Negro et al. 76came to similar conclusions
in a study of patients with asthma.
Two case reports”‘, ” suggest that ranitidine also
inhibits theophylline clearance. However, it is diffi-
cult to draw conclusions from these reports; both con-
cern elderly patients undergoing substantial co-med-
ication.
ORAL CONTRACEPTIVES
It has been suggested that oral contraceptive ste-
roids may inhibit the hepatic mixed-function oxi-
dases and that this may result in lower theophylline
clearance. Indeed Tomatore et a1.83reported signifi-
cantly lower (average of 34%) theophylline clearance
in eight nonsmoking users of oral contraceptives, as
compared with eight nonusers. In a second report, the
same investigatorss4 reported a 28% decrease in clear-
ance in ten nonsmoking women who used oral con-
traceptives and a 32% decrease in a group of smokers.
Similar results were reported by Roberts et al.‘? the-
with theophylline pharmacokinetics 739
ophylline clearance was 29% lower in women using
oral contraceptives. On the contrary, MacLeod et a1.86
recently found no difference in theophylline clearance
in ten adolescent females (mean age of 17 years -+ 1
year) taking combined low-dose oral contraceptives
for 3 months to 9 months.
OTHER DRUGS
Several other drugs that are used more or less fre-
quently by patients with asthma have an influence on
theophylline pharmacokinetics.
Barbiturates and several of the antiepileptic drugs
are known to induce hepatic microsomal enzymes. An
increase in theophylline clearance was described when
phenobarbital was administered (17% reported Piaf-
sky et a1.87;33%, by Landay et al.“). When seco-
barbital is used, the figure is 340%,89 and for pen-
tobarbit(zl the figure is 95%.90
Likewise, the anticonvulsant phenytoin can mark-
edly increase theophylline clearance. The following
figures Eave been reported: 45%,9’ 53%,9’ and 73%.93
Similar results were published by Sklar and Wagner.”
There is thus no doubt that careful theophylline mon-
itoring and dosage adjustment are required during phe-
nytoin therapy.
A number of xanthine derivatives, including caf-
feine and allopurinol, may interfere with theophylline
elimination because of common metabolic pathways.
Until .now, caffeine, as an important component of
the diet, has not been shown to interact with theoph-
ylline in a clinically important way.“. 9h
Allopurinol (hypoxanthine derivative), as a com-
petitive inhibitor of xanthine oxidase, may also in-
terfere with theophylline metabolism. Seven-day stud-
ies using standard doses did not show an effect.97.y8
However, a 28-day course of doubled doses of allo-
purinol did decrease theophylline clearance by 2 1%.99
Nonselective /3-adrenoceptor blockers (P-sympath-
icolytics) are contraindicated for patients with bron-
chial obstruction. Nevertheless, Conrad and Nymanloo
studied propranolol (in healthy subjects) and found a
33% reduction in theophylline clearance during co-
medication. Metoprolol had no effect.
CONCLlJSlON
A number of drugs frequently coadministered with
theophylline have been shown to interfere with the-
ophylline pharmacokinetics. This number is still in-
creasing.
Adjustment of the dose, preferably guided by serum
theophylline monitoring, may in some cases be re-
quired fcr optimum therapy and to avoid toxic or
subtherapeutic serum concentration.
740 Jonkmar
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