Arch Pharm Res Vol 31, No 7, 938-944, 2008
The Effect of Coenzyme Q10 on the Pharmacokinetic
Parameters of Theophylline
Rengarajan Baskaran, Srinivasan Shanmugam, Santhoshkumar Nagayya-Sriraman, Ju Hyun Kim,
Tae Chun Jeong, Chul Soon Yong, Han-Gon Choi, and Bong Kyu Yoo
College of Pharmacy, Yeungnam University, Kyungbuk 712-749, Korea
(Received April 1, 2008/Revised May 27, 2008/Accepted June 12, 2008)
Interaction of a drug with other drugs and dietary supplements is becoming an emerging issue
for patients and health insurance authorities due to awareness of adverse drug event. In this
study, we examined the effects of coenzyme Q10 (CoQ10), one of the most popular dietary
supplements, on the pharmacokinetic parameters of theophylline in rats. The pharmacokinetic
parameters of theophylline changed significantly when the drug was administered after five
consecutive days of pretreatment with CoQ10. Time to reach maximum plasma concentration
of theophylline delayed when the drug was administered after the pretreatment with CoQ10.
Maximum plasma concentration and area under the curve of theophylline were about two-fold
increased and other pharmacokinetic parameters such as half-life and volume of distribution
were also changed significantly. Therefore, although CoQ10 is generally considered a safe
dietary supplement, it appears that patients on theophylline therapy should use caution when
they take CoQ10.
Key words: Theophylline, Coenzyme Q10, Pharmacokinetic parameters, Protein binding,
Coenzyme Q10 (CoQ10) is a fat-soluble quinone com-
pound commonly known as ubiquinone. The chemical
structure of CoQ10 is 2,3-dimethoxy-5-methyl-6-decaprenyl-
1,4-benzoquinone in all-trans configuration (Fig. 1,
Greenberg and Frishman, 1990; Tran et al., 2001).
CoQ10 is found anywhere in the body, and is found in
high concentrations in tissues with high energy turnover
such as heart, brain, liver, and kidney (Bonakdar and
Guarneri 2005; Leonhauser et al., 1962; Sun et al., 1992).
CoQ10 has a fundamental role in cellular bioenergetics as
a cofactor of the oxidative phosphorylation process in the
mitochondria for the production of ATP. Furthermore,
CoQ10 in its reduced form (ubiquinol) is a potent lipophilic
antioxidant and is capable of recycling and regenerating
other antioxidants such as tocopherol and ascorbate
(Hyun et al., 2006). Other important function of CoQ10
includes expression of genes involved in the cell signaling
CoQ10 is available as over-the-counter dietary supple-
ment and is one of the most commonly used supplements
in most developed countries. Potential benefits of CoQ10
supplementation have been recognized in the manage-
ment of patients with cardiovascular and neurodegen-
erative diseases such as heart failure and Parkinson’s
diseases (Singh et al., 2007; Littarru and Tiano, 2005;
Bonuccelli and Del Dotto, 2006; Janson, 2006; Buettner
et al., 2007; Shults et al., 2004; Shults and Haas, 2005). A
number of randomized controlled trials were performed
and found improvement in several clinical parameters
related to heart failure, including frequency of hospitaliza-
Correspondence to: Bong Kyu Yoo, College of Pharmacy, Yeung-
nam University, 214-1 Dae-dong, Kyungsan, Kyungbuk, 712-749,
Tel: 82-53-810-2822, Fax: 82-53-810-4654
Fig. 1. Chemical structure of coenzyme Q10
The Effect of Coenzyme Q10 on the Pharmacokinetic Parameters of Theophylline 939
tion, dyspnea, and edema. CoQ10 supplementation has
also been reported to restore plasma CoQ10 levels in
patients receiving statin therapy for the treatment of
dyslipidemia (Sassi et al., 1994; Laaksonen et al., 1994;
Young et al., 2007). Recently, CoQ10 is gaining popularity
as an important nutrient that may help in the treatment of
various other diseases such as oncologic and endocri-
nologic disorders (Roffe et al., 2004; Ratnam et al., 2006;
Conklin 2005; Hodgson et al., 2002).
CoQ10 is generally considered safe. However, gastroin-
testinal discomfort associated with the use of CoQ10 is
not rare and potential interactions with warfarin causing
decreased anticoagulation activity have been reported in
case studies (Landbo and Almdal, 1998). Interaction of a
drug with other drugs and dietary supplements is becom-
ing an emerging issue for patients and health insurance
authorities due to awareness of adverse drug event.
However, the interaction of CoQ10 and other commonly
prescribed drug has not been extensively studied. To
date, warfarin is the only prescription drug which demon-
strated detrimental outcome with concurrent use of CoQ10.
Although exact mechanism of the interaction is not fully
elucidated, CoQ10 increases metabolism of warfarin by
selective activation of cytochrome P450 enzymes in rat
and human liver microsomes, which are also involved in
the metabolism of theophylline (Tjia et al., 1996; Zhou et
al., 2005; Kaminsky and Zhang 1997). Theophylline is a
medication commonly used for the treatment of asthma
and chronic obstructive pulmonary disease as a long-term
treatment. Furthermore, theophylline has narrow therapeutic
index which requires close monitoring of plasma level
during therapy. In this study, therefore, we examined the
effects of CoQ10 on the pharmacokinetic parameters of
theophylline. We also studied the effect of CoQ10 on pro-
tein binding of the drug in pooled rat plasma and relative
enzyme activity of cytochrome P450 1A1 and 1A2.
MATERIALS AND METHODS
Theophylline, 7-(β-hydroxypropyl)-theophylline, ethoxy-
resorufin, and methoxyresorufin were obtained from Sigma.
CoQ10 was kindly donated by Yuhan Corporation (Seoul,
Korea), and was handled as of light-protected during all
experimental precedures. Acetonitrile, dichloromethane,
dimethylformamide, sodium phosphate monobasic, and
sodium phosphate dibasic were purchased from Sigma-
Aldrich. All other chemicals were analytical grade and
were used without further purification.
Nine-week-old male Sprague Dawley rats weighing
approximately 250 g were supplied by OrientBio (Seoul,
Korea) and housed in groups not exceeding six per cage
and maintained under standard conditions. Food and tap
water were available ad libitum. The acclimation period
was one week before the experimental procedure with a
dark/light cycle of 12:12 at a temperature of 23 ± 2oC.
Animal experiments were carried out according to the
guidelines for animal use in toxicology and current Korean
laws when the experiment was carried out.
Rats were randomly separated into three test groups
and a control group (n=6). Five days before the admini-
stration of theophylline, rats in each test group were pre-
treated with oral administration of CoQ10 dissolved into
corn oil with slight warming. Doses of CoQ10 ranged from
300 to 1200 mg/kg. Rats in the control group received the
same amount of corn oil without CoQ10. On the sixth day,
all rats were administered with a single dose of theophyl-
line (per oral, 15 mg/kg) as of dissolved into 0.9% saline
(4.5 mg/mL) in addition to the CoQ10 regimen that each
rat was receiving. Blood samples of 0.3 ml were serially
withdrawn under anesthesia via subclavian vein into small
heparinized Eppendorf tubes at 0, 0.5, 1, 2, 3, 6, 9, 12,
24, 36, and 48 h after theophylline administration. The
blood samples were immediately centrifuged at 3000 g for
10 min, and the plasma was taken out and stored at -20
oC until HPLC assay of theophylline concentration. Statis-
tical analysis was performed using the SPSS 12.1 pro-
gram and considered significant when p-value was less
HPLC assay of theophylline in rat plasma
Concentration of theophylline in plasma sample was
assayed by HPLC with a slight modification on the method
described by Koch (Koch et al., 2001). Briefly, the frozen
plasma samples were thawed at room temperature and
aliquots of 100 mL were spiked with 50 mL of internal
standard (7-β-hydroxypropyl-theophylline in ethanol, 25
mg/mL). After a few seconds of vortex-mixing, 1.8 mL of
methylene chloride was added for deproteination of the
plasma sample. Precipitation of the protein was facilitated
by centrifugation using Eppendorf microcentrifuge for 1
min at 13,000 g and the resultant clear supernatant (1
mL) was transferred to Eppendorf tube and dried in
vacuum using centrifugal evaporator. The dried residue
was reconstituted by 200 mL of mobile phase (mixture of
0.05 M phosphate buffer and acetonitrile (81:19), pH 5.0)
and injected to HPLC system (Shimadzu, Japan) by using
autoinjector (Intelligent Sampler AS-950-10, Jasco, Japan).
The plasma level of unmetabolized theophylline was
assayed by the HPLC system equipped with Class VP
computer software, LC 10AD VP pump, and SPD 10A VP
UV-VIS detector at 274 nm. Column was Inertsil ODS-3
(4.6×150 mm, GL Science Inc, Japan) and mobile phase
consisted of a mixture of 0.05 M phosphate buffer (sodium
940R. Baskaran et al.
phosphate monobasic and sodium phosphate dibasic)
and acetonitrile (81:19, v/v) adjusted to pH 5.0 with phos-
phoric acid. Flow rate was 0.8 mL/min and the injection
volume of the sample was 20 mL. Before measuring the
plasma level of theophylline by HPLC, validation of the
assay was performed in the range of 50-1500 ng/mL. The
pharmacokinetic parameters were calculated using the
software WinNonlin Standard Edition Version 1.1 by non-
Protein binding study in rat plasma
To an aliquot of 900 µL of pooled rat plasma was added
100 µL of either 0.9% normal saline or CoQ10 solution at
various concentrations to make 0, 1, 10, 20, and 30 µg/mL
of CoQ10 in the final solution. Since CoQ10 is insoluble in
water, it was dissolved into dimethylformamide and appro-
priately diluted with the normal saline. Volume of dimethyl-
formamide needed was adjusted to make 0.6% v/v of the
organic solvent in the final solution. To this solution, 180
µL of theophylline solution in distilled water (100 µg/mL)
was added to yield about 15.25 µg/mL of the drug in the
final test sample and allowed to incubate at 37oC in water
bath with gentle shaking. After 10 min, the test sample was
transferred into Amicon ultrafiltration device (Millipore,
U.S.A.; MWCO 10,000 g/mole) and centrifuged at 4000 g
for 15 min. The volume of retentate was always about
28% of the total volume applied in the ultrafiltration device.
Aliquot of retentate was taken and processed for theo-
phylline analysis by HPLC as described above. Percentage
of protein binding was calculated by the following equation:
% protein binding = 100 × theophylline in retentate/theo-
phylline total). Preliminary experiment of the protein bind-
ing was performed in 0.6% dimethylformamide solution in
the normal saline.
Cytochrome P450 enzyme activity
Enzyme activities of cytochrome P450 1A1 and 1A2
were measured using ethoxyresorufin-O-deethylase (EROD)
and methoxyresorufin-O-demethylase (MROD) activity
assays, respectively. EROD and MROD activities were
determined from the rate of formation of resorufin from
either ethoxyresorufin or methoxyresorufin as described
by Blank with a slight modification (Blank et al., 1987).
CoQ10 (0, 1, 10, 20, 30 mg/mL) was preincubated with
rat liver microsomes for 20 min at 37oC. The formation of
resorufin was monitored by fluorescence spectroscopy at
excitation and emission wavelengths of 550 and 585 nm,
Validation of HPLC assay was performed by repeating
five times a day on the first day and for five consecutive
days. Limit of quantification (LOQ) was 50 ng/mL and
precisions of intra-day and inter-day at the LOQ were less
than 15%. Accuracies of intra-day and inter-day were
within about ±15%, showing an acceptable variation for
the quantification of theophylline in rat plasma sample.
Linearity of calibration curve for determination of theophyl-
line was r2=0.9996, and equation of the curve was
y=0.085x+0.042 in the range of from 50 to 1500 ng/mL.
The retention times for theophylline and internal standard
(7-β-hydroxypropyl-theophylline) were 3.6 min and 4.9
Table I summarized pharmacokinetic parameters of
theophylline in rats after a single oral administration with
15 mg/kg dose of the drug. The pharmacokinetic para-
meters of theophylline changed significantly when the
drug was administered after five consecutive days of pre-
treatment with CoQ10. Time to reach maximum plasma
concentration (Tmax) of theophylline was about 0.5 h when
the drug was administered without CoQ10, while it was
delayed to 2-3 h when administered after the pretreatment
with CoQ10. Maximum plasma concentration (Cmax) was
Table I. Pharmacokinetic parameters of theophylline in rat following a single oral administration of 15 mg/kg after five consecutive days of
pretreatment with coenzyme Q10 (n=6)
pretreatment a with CoQ10
600 mg/kg 300 mg/kg 1200 mg/kg
AUC0-48 (mg ×min /mL)
24.44 ± 1.81
46.19 ± 5.12
28.63 ± 1.24
21.16 ± 0.21
29.97 ± 1.65**
91.30 ± 8.04**
25.92 ± 0.97**
20.40 ± 0.01**
214.68 ± 1.51**
120.67 ± 6.34**
225.09 ± 1.54**
220.27 ± 0.03**
211.51 ± 1.38**
117.42 ± 4.26**
227.76 ± 2.32*
220.37 ± 0.05**
aTheophylline (15mg/kg) was orally administered five consecutive days of oral administration of CoQ10 suspended into corn oil, AUC = area under
the curve, Cmax =maximum plasma concentration, CL = clearance, F=bioavailability, Ke = elimination constant, Tmax =time to reach maximum
plasma concentration, Vd = distribution volume, *p < 0.05 in comparison to control group. **p < 0.01 in comparison to control group.
The Effect of Coenzyme Q10 on the Pharmacokinetic Parameters of Theophylline941
4.44 ± 1.81 µg/mL following a single oral administration of
the drug without CoQ10. The Cmax increased significantly
when theophylline was administered after the pretreat-
ment with CoQ10, showing 9.97 ± 1.65, 16.68 ± 1.51, and
11.51 ± 1.38 µg/mL for 300, 600, and 1200 mg/kg dose of
CoQ10, respectively. These changes represent 125, 230,
and 160% increase compared to the control group in the
corresponding order. Area under the curve (AUC) also
increased significantly when the rats were pretreated with
CoQ10 and administered with the drug. The change of
the AUC was not dose-dependent to CoQ10 and was
most remarkable in 600 mg/kg group. Half-life (t1/2) was
reduced from 8.63 ± 1.24 h to about 5-8 h, and significant
decrease of apparent volumes of distribution (Vd/F) was
also observed in the CoQ10 pretreatment groups. Fig. 2
shows concentration versus time profile of theophylline in
our pharmacokinetic study.
Protein binding study of theophylline was performed
using Amicon ultrafiltration device in the absence and
presence of CoQ10. Proportion of theophylline bound to
pooled rat plasma protein was about 40.4 ± 2.4% in the
absence of CoQ10 (Table II). Dimethylformamide used to
dissolve CoQ10 did not affect percentage of the drug
bound to rat plasma protein at 0.6% v/v concentration. In
the presence of CoQ10, protein binding of the drug was
slightly increased to about 42-44% for the entire CoQ10
concentration range tested (1-30 µg/mL), but statistically
significant difference was not found (p-value > 0.172).
Cytochrome P450 activity study showed no significant
difference in the relative activity of EROD and MROD in
the CoQ10 concentration range tested (Fig. 3, p-value >
0.05 for all concentrations). At 1 µg/mL of CoQ10 con-
centration, the relative activities of MROD and EROD
were 98.2% and 97.4%, respectively. Even at the highest
concentration of CoQ10 (30 mg/mL), the relative activities
of EROD and MROD were 102.4% and 103.2% in the
Dietary supplements are available as over-the-counter
status and becoming increasingly popular for the man-
agement of various illnesses. Many of these supplements
have demonstrated pharmacologic actions used to
produce therapeutic results (Gardiner et al., 2006). Even
supplements that do not have a documented pharmacologic
action can affect the absorption, distribution, metabolism,
and excretion of other drugs. Patients with heart failure,
Fig. 2. Concentration versus time in rat plasma following a single oral
administration of 15 mg/kg theophylline after pretreatment with
coenzyme Q10 for five consecutive days. Rats were orally pretreated
for five consecutive days with coenzyme Q10 dissolved into corn oil.
control (×), 300 mg/kg of coenzyme Q10 (□), 600 mg/kg of coenzyme
Q10 (△), 1200 mg/kg of coenzyme Q10 (○). The arithmetic means
and standard deviations from six experiments were shown here.
Table II. Effect of Coenzyme Q10 on protein binding of theophyllinea
0.6% v/v dimethylformamide in
0.9% normal saline
protein binding (%) 40.4 ± 2.440.8 ± 4.9b
42.3 ± 1.6b
43.0 ± 4.7b
42.5 ± 3.9b
43.7 ± 2.8b
Data are presented as estimated mean value ± S.D. for n=3,
dimethylformamide and the concentration of the organic solvent in the final solution was fixed to 0.6% v/v, CoQ10=coenzyme Q10, bnot statistically
significant compared to 0.9% normal saline (p > 0.172).
acoenzyme Q10 was dissolved into 0.9% normal saline with the aid of
Fig. 3. Effect of coenzyme Q10 on relative activity of cytochrome P450
enzymes: EROD and MROD. EROD = methoxyresorufin-O-demethyl-
ase, MROD = ethoxyresorufin-O-deethylase
942R. Baskaran et al.
cardiac arrhythmia, or seizure disorders often report adverse
drug event associated with dietary supplement-drug in-
teraction (Gardiner et al., 2008). CoQ10 is commonly used
by geriatric patients who are at high risk of such interac-
tion due to their established cardiovascular diseases and
multiple medications that they are already on. However,
due to general misbelief on its safety profile, CoQ10 did
not receive proper attention about potential interaction
with other prescription drugs.
Recently, high doses of coenzyme Q10 are tried for the
treatment of various diseases such as Parkinson’s disease,
Huntington’s disease, and amyotrophic lateral sclerosis.
The dosage under clinical trials is currently up to 3,000
mg/day for human use as reported by other researchers
(Levy et al., 2006; Ferrante et al., 2005). For animal study,
however, the dosage was up to 20,000 mg/kg/day as
reported by previous researchers (Yang et al., 2005; Smith
et al., 2006). In this study, we examined the pharmacokinetic
parameters of theophylline following a single oral admini-
stration in rats after five consecutive days of pretreatment
with CoQ10 (dosage: 300-1200 mg/kg) and found that
CoQ10 significantly increased Cmax and AUC of theophyl-
line as much as two times or more. When rats were
pretreated with CoQ10 beyond daily dose of greater than
600 mg/kg, Cmax of the drug increased to almost three
times of that found in the control group. Tmax, t1/2, and
other pharmacokinetic parameters were also changed
significantly in rats pretreated with CoQ10. It is not clear
why Tmax, Cmax, and AUC of theophylline were altered by
CoQ10 pretreatment at this time. However, the delay in
Tmax appears to be attributable to fatty nature of CoQ10,
and increase in Cmax and AUC seems to be associated
with decrease in the clearance of the drug. Decrease in
Vd/F also appears to be related with the diminished
clearance of the drug. Theophylline is a prescription drug
commonly used for the treatment of asthma and chronic
obstructive pulmonary disease as a long-term treatment in
geriatric patients. Furthermore, theophylline has a narrow
therapeutic index which requires close monitoring of
plasma level during therapy. Although therapeutic window
of theophylline is generally considered 5-20 µg/mL (Tang
et al., 2007; Brunton et al., 2005), AHFS suggests closer
plasma level monitoring to maintain 10-15 µg/mL (AHFS
2007). When peak serum theophylline concentrations
exceed 20 µg/mL, theophylline produces a wide range of
adverse reactions including persistent vomiting, cardiac
arrhythmias, and intractable seizures which can be lethal.
Therefore, it appears that patients on theophylline therapy
should use caution when they take CoQ10 as a dietary
Bioavailability of theophylline is reported above 95% for
most commercially available dosage forms (Brunton et al.,
2005; AHFS, 2007). Formulation of the drug administered
to rats in our experiment was an aqueous solution.
Therefore, the increase of Cmax and AUC found in our
experiment did not appear to be caused by alteration in
absorption process through the gastrointestinal tract. In
order to find out the reason for this interaction of CoQ10
and theophylline, we performed protein binding study.
Proportion of theophylline bound to rat plasma protein
was about 40%, which is consistent with the report in the
textbooks (Brunton et al., 2005; AHFS, 2007). In our
protein binding study, there was no significant change on
protein binding behavior of the drug throughout the
concentration range of CoQ10 at a fixed level of 15.25 µg/
mL theophylline. Taking into consideration that the
concentration of the drug in in vivo study with rat was less
than 15.25 µg/mL, the effect of CoQ10 on protein binding
would be even less than that found in in vitro. Therefore,
the effect of protein binding on Vd/F of the drug would be
Unwanted interactions of a drug with other drugs or
dietary supplements are usually related with pharma-
cokinetic alterations in various steps such as absorption,
distribution, metabolism, and excretion. We found that
concomitant use of CoQ10 and theophylline caused signi-
ficant change on pharmacokinetic parameters of theophyl-
line. Limitation of this study, however, was that our study
design could not discriminate whether the alteration was
due to pretreatment effect or coadministration effect.
Therefore, further study is warranted to elucidate what
really causes the pharmacokinetic alteration.
We studied the pharmacokinetic parameters of theo-
phylline when the drug was orally administered after five
consecutive days of pretreatment with CoQ10. Cmax and
AUC of theophylline were about two-fold increased in rats
pretreated with CoQ10 and other pharmacokinetic para-
meters such as Tmax, t1/2, and Vd/F were also changed
significantly. Therefore, although CoQ10 is generally con-
sidered safe, it appears that patients on CoQ10 as a
dietary supplement should use caution when they begin
to take theophylline.
This work was supported by the grant from Korea
Research Foundation for the Institute for Drug Research,
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