The Effect of Coenzyme Q10 on the Pharmacokinetic ... - Springer Link

Arch Pharm Res Vol 31, No 7, 938-944, 2008 DOI 10.1007/s12272-001-1250-1

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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, Cytochrome P450,

INTRODUCTION Coenzyme Q10 (CoQ10) is a fat-soluble quinone compound commonly known as ubiquinone. The chemical structure of CoQ10 is 2,3-dimethoxy-5-methyl-6-decaprenyl1,4-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 Correspondence to: Bong Kyu Yoo, College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Kyungsan, Kyungbuk, 712-749, Korea Tel: 82-53-810-2822, Fax: 82-53-810-4654 E-mail: [email protected]

Fig. 1. Chemical structure of coenzyme Q10

(Crane 2001). CoQ10 is available as over-the-counter dietary supplement and is one of the most commonly used supplements in most developed countries. Potential benefits of CoQ10 supplementation have been recognized in the management of patients with cardiovascular and neurodegenerative 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-

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The Effect of Coenzyme Q10 on the Pharmacokinetic Parameters of Theophylline

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 endocrinologic disorders (Roffe et al., 2004; Ratnam et al., 2006; Conklin 2005; Hodgson et al., 2002). CoQ10 is generally considered safe. However, gastrointestinal 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 becoming 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 demonstrated 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 protein binding of the drug in pooled rat plasma and relative enzyme activity of cytochrome P450 1A1 and 1A2.

MATERIALS AND METHODS Materials Theophylline, 7-(β-hydroxypropyl)-theophylline, ethoxyresorufin, 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 SigmaAldrich. All other chemicals were analytical grade and were used without further purification. Animal study Nine-week-old male Sprague Dawley rats weighing approximately 250 g were supplied by OrientBio (Seoul,

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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 administration of theophylline, rats in each test group were pretreated 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 theophylline (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 o C until HPLC assay of theophylline concentration. Statistical analysis was performed using the SPSS 12.1 program and considered significant when p-value was less than 0.05.

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

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phosphate monobasic and sodium phosphate dibasic) and acetonitrile (81:19, v/v) adjusted to pH 5.0 with phosphoric 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 noncompartmental method.

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 appropriately diluted with the normal saline. Volume of dimethylformamide 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 theophylline analysis by HPLC as described above. Percentage of protein binding was calculated by the following equation: % protein binding = 100 × theophylline in retentate/theophylline total). Preliminary experiment of the protein binding 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, respectively.

RESULTS 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 theophylline 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 min, respectively. Table I summarized pharmacokinetic parameters of theophylline in rats after a single oral administration with 15 mg/kg dose of the drug. 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 (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) parameters Tmax (h) Cmax (µg/mL) AUC0-48 (mg ×min /mL) t1/2 (h) Vd/F (L/kg) CL/F (mL/min×kg) Ke (h-1) a

control 20.5 24.44 ± 1.81 46.19 ± 5.12 28.63 ± 1.24 21.16 ± 0.21 0.09 0.08

300 mg/kg

pretreatment a with CoQ10 600 mg/kg

1200 mg/kg

22** 29.97 ± 1.65** 91.30 ± 8.04** 25.92 ± 0.97** 20.40 ± 0.01** 20.05* 20.12*

222** 214.68 ± 1.51** 120.67 ± 6.34** 225.09 ± 1.54** 220.27 ± 0.03** 220.04** 220.14**2

223** 211.51 ± 1.38** 117.42 ± 4.26** 227.76 ± 2.32* 220.37 ± 0.05** 220.03** 220.09

Theophylline (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.


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 pretreatment 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

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.

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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 concentration, 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 corresponding order.

DISCUSSION Dietary supplements are available as over-the-counter status and becoming increasingly popular for the management 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. 3. Effect of coenzyme Q10 on relative activity of cytochrome P450 enzymes: EROD and MROD. EROD = methoxyresorufin-O-demethylase, MROD = ethoxyresorufin-O-deethylase

Table II. Effect of Coenzyme Q10 on protein binding of theophyllinea

protein binding (%)

0.9% normal saline

0.6% v/v dimethylformamide in 0.9% normal saline

1 µg/mL CoQ10

10 µg/mL CoQ10

20 µg/mL CoQ10

30 µg/mL CoQ10

40.4 ± 2.4

40.8 ± 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, acoenzyme Q10 was dissolved into 0.9% normal saline with the aid of 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).

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cardiac arrhythmia, or seizure disorders often report adverse drug event associated with dietary supplement-drug interaction (Gardiner et al., 2008). CoQ10 is commonly used by geriatric patients who are at high risk of such interaction 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 administration 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 theophylline 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 supplement. Bioavailability of theophylline is reported above 95% for most commercially available dosage forms (Brunton et al., 2005; AHFS, 2007). Formulation of the drug administered

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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 negligible. Unwanted interactions of a drug with other drugs or dietary supplements are usually related with pharmacokinetic alterations in various steps such as absorption, distribution, metabolism, and excretion. We found that concomitant use of CoQ10 and theophylline caused significant change on pharmacokinetic parameters of theophylline. 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.

CONCLUSION We studied the pharmacokinetic parameters of theophylline 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 parameters such as Tmax, t1/2, and Vd/F were also changed significantly. Therefore, although CoQ10 is generally considered safe, it appears that patients on CoQ10 as a dietary supplement should use caution when they begin to take theophylline.

ACKNOWLEDGEMENTS This work was supported by the grant from Korea Research Foundation for the Institute for Drug Research, Yeungnam University (KRF-2006-005-J01102).

REFERENCES AHFS (American Society of Health-System Pharmacists), AHFS drug information. Board of the AHFS, Bethesda


(2007). Blank, J., Tucker, A., Sweatlock, J., Gasiewicz, T., and Luster, M., Alpha-naphthoflavone antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced murine lymphocyte ethoxyresorufinO-deethylase activity and immunosuppression. Mol. Pharmacol., 32, 169-172 (1987). Bonakdar, R. and Guarneri, E., Coenzyme Q10. Am. Fam. Phys., 72, 1065-1070 (2005). Bonuccelli, U. and Del Dotto, P., New pharmacologic horizons in the treatment of Parkinson disease. Neurology, 67(7 Suppl 2), S30-38 (2006). Brunton, R., Lazo, J., and Parker, K., Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York (2005). Buettner, C., Phillips, R., Davis, R., Gardiner, P., and Mittleman, M., Use of dietary supplements among United States adults with coronary artery disease and atherosclerotic risks. Am. J. Cardiol., 99, 661-666 (2007). Conklin, K., Coenzyme q10 for prevention of anthracyclineinduced cardiotoxicity. Integr. Cancer Ther., 4, 110-130 (2005). Crane, F., Biochemical functions of coenzyme Q10. J. Am. Coll. Nutr., 20, 591-598 (2001). Ferrante, K., Shefner, J., Zhang, H., Betensky, R., O'Brien, M., Yu, H., Fantasia, M., Taft, J., Beal, M., Traynor, B., Newhall, K., Donofrio, P., Caress, J., Ashburn, C., Freiberg, B., O'Neill, C., Paladenech, C., Walker, T., Pestronk, A., Abrams, B., Florence, J., Renna, R., Schierbecker, J., Malkus, B., and Cudkowicz, M., Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS. Neurology, 65, 1834-1836 (2005). Gardiner, P., Graham, R., Legedza, A., Eisenberg, D., and Phillips, S., Factors associated with dietary supplement use among prescription medication users. Arch. Intern. Med., 166, 1968-1974 (2006). Gardiner, P., Phillips, R., and Shaughnessy, A., Herbal and dietary supplement-drug interactions in patients with chronic illnesses. Am. Fam. Physician, 77, 73-78 (2008). Greenberg, S. and Frishman, W. Co-enzyme Q10: a new drug for cardiovascular disease. J. Clin. Pharmacol., 30, 596-608 (1990). Hodgson, J., Watts, G., Playford, D., Burke, V., and Croft, K., Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur. J. Clin. Nutr., 56, 1137-1142 (2002). Hyun, D., Emerson, S., Jo, D., Mattson, M., and de Cabo, R., Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc. Natl. Acad. Sci. USA, 103, 19908-19912 (2006). Janson, M., Orthomolecular medicine: the therapeutic use of dietary supplements for anti-aging. Clin. Interv. Aging, 1, 261265 (2006). Kaminsky, L. and Zhang, Z., Human P450 metabolism of warfarin. Pharmacol. Ther., 73, 67-74 (1997). Koch, K., Ricci, B., Hedayetullah, N., Jewell, D., and Kersey, K.,

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Effect of alosetron on theophylline pharmacokinetics. Br. J. Clin. Pharmacol., 52, 596-600 (2001). Laaksonen, R., Ojala, J., Tikkanen, M., and Himberg, J., Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur. J. Clin. Pharmacol., 46, 313-317 (1994). Landbo, C. and Almdal, T., Interaction between warfarin and coenzyme Q10. Ugeskr. Laeger., 160, 3226-3227 (1998). Leonhauser, S., Lebold, K., Krisch, K., Standinger, H., Gale, F., Page, A. Jr., and Folkers, K., Arch. Biochem. Biophys., 96, 580-586 (1962). Levy, G., Kaufmann, P., Buchsbaum, R., Montes, J., Barsdorf, A., Arbing, R., Battista, V., Zhou, X., Mitsumoto, H., Levin, B., and Thompson, J., A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS. Neurology, 66, 660-663 (2006). Littarru, G. and Tiano, L., Clinical aspects of coenzyme Q10: an update. Curr. Opin. Clin. Nutr. Metab. Care, 8, 641-646 (2005). Ratnam, D., Ankola, D., Bhardwaj, V., Sahana, D., and Kumar, M., Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. J. Control. Release, 113, 189-207 (2006). Roffe, L., Schmidt, K., and Ernst, E., Efficacy of coenzyme Q10 for improved tolerability of cancer treatments: a systematic review. J. Clin. Oncol., 22, 4418-4424 (2004). Sassi, S., Genova, M., and Lenaz, G., Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int. J. Clin. Lab. Res., 24, 171-176 (1994). Shults, C. and Haas, R., Clinical trials of coenzyme Q10 in neurological disorders. Biofactors, 25, 117-126 (2005). Shults, C., Flint Beal, M., Song, D., and Fontaine, D., Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease. Exp. Neurol., 188, 491-494 (2004). Singh, U., Devaraj, S., and Jialal, I., Coenzyme Q10 supplementation and heart failure. Nutr. Rev., 65(6 Pt 1), 286-293 (2007). Smith, K., Matson, S., Matson, W., Cormier, K., Del Signore, S., Hagerty, S., Stack, E., Ryu, H., and Ferrante, R., Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. Biochim. Biophys. Acta, 1762, 616-626 (2006). Sun, I., Sun, E., Crane, F., Morro, D., Lindgren, A., and Low, H., Requirement for coenzyme Q in plasma membrane electron transport. Proc. Natl. Acad. Sci. USA, 89, 11126-11130 (1992). Tang, J., Sun, J., Zhang, Y., Li, L., Cui, F., and He, Z., Herb-drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats. Food Chem. Toxicol., 45, 2441-2445 (2007). Tjia, J., Colbert, J., and Back, D., Theophylline metabolism in human liver microsomes: inhibition studies. J. Pharmacol. Exp. Ther., 276, 912-917 (1996).

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Tran, M., Mitchell, T., Kennedy, D., and Giles, J., Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy, 21, 797-806 (2001). Yang, H., Lin, S., Huang, S., and Chou, H., Acute administration of red yeast rice (Monascus purpureus) depletes tissue coenzyme Q(10) levels in ICR mice. Br. J. Nutr., 93, 131-135 (2005).

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Young, J., Florkowski, C., Molyneux, S., McEwan, R., Frampton, C., George, P., and Scott, R., Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am. J. Cardiol., 100, 1400-1403 (2007). Zhou, Q., Zhou, S., and Chan, E., Effect of coenzyme Q10 on warfarin hydroxylation in rat and human liver microsomes. Curr. Drug Metab., 6, 67-81 (2005).