Coenzyme Q₁₀ (CoQ₁₀) is an endogenous proenzyme synthesized naturally in the human body.¹ Because of its ubiquitous presence in nature and its quinone structure, CoQ₁₀ is also known as ubiquinone (Figure 79-1). The two major physiologic actions of CoQ₁₀ are (1) as a cofactor in the production of adenosine triphosphate (ATP), and (2) as an antioxidant. Because most cellular functions depend on an adequate supply of ATP, CoQ₁₀ is essential for the health of virtually all human tissues and organs. Cellularly, the highest concentration of CoQ₁₀ is found in the inner mitochondrial membrane, where it facilitates energy production, but CoQ₁₀ is found in the cell membranes of many organelles where it plays a role in membrane stability.² CoQ₁₀ is the only endogenously synthesized lipid soluble antioxidant.³ In its role in electron transport, the CoQ₁₀ molecule continuously goes through an oxidation-reduction cycle. As it accepts electrons, it becomes reduced to ubiquinol. As it gives up electrons, it becomes oxidized to ubiquinone. In contrast to other antioxidants, this compound inhibits both the initiation and the propagation of lipid and protein oxidation. In its reduced form, ubiquinol, the CoQ₁₀ molecule holds electrons rather loosely, so the CoQ₁₀ molecule will quite easily give up one or both electrons and, thus, act as an antioxidant. It is especially protective against the oxidation of bases of mitochondrial DNA. In addition, ubiquinol is responsible for regenerating vitamin E from the α-tocopheroxyl radical and, thereby interfering with the propagation step of lipid peroxidation.

FIGURE 79-1 Ubiquinone

Biosynthesis of CoQ₁₀ starts from acetyl coenzyme A (CoA) and flows through a multistep process of the mevalonate pathway to produce farnesyl-PP, the direct precursor for not only CoQ₁₀, but also cholesterol, dolichol, and isoprenylated proteins. The long isoprenoid side-chain of CoQ₁₀ is synthesized by trans-prenyltransferase, which condenses farnesyl-PP with several molecules of isopentenyl-PP, all in the trans configuration. The next step involves condensation of this polyisoprenoid side-chain with 4-hydroxybenzoate, catalyzed by polyprenyl-4-hydroxybenzoate transferase. Hydroxybenzoate is synthesized from tyrosine or phenylalanine. In addition to their presence in mitochondria, these initial two reactions also occur in the endoplasmic reticulum and peroxisomes, indicating multiple sites of synthesis in human cells. Nonetheless, numerous conditions are now known to arise in which the body’s synthetic capacity is insufficient to meet CoQ₁₀ requirements. Susceptibility to CoQ₁₀ deficiency appears to be greatest in cells that are the most metabolically active, such as the brain and heart. Tissue deficiencies or subnormal serum levels of CoQ₁₀ have been reported to occur in a wide range of medical conditions and decline with advancing age.³

A need for supplemental CoQ₁₀ could theoretically result from the following:

• Impaired CoQ₁₀ synthesis due to nutritional deficiencies

• A genetic or acquired defect in CoQ₁₀ biosynthesis or utilization

• Increased tissue needs resulting from a particular illness

• The requirement to prevent the side effects of medical intervention

Because oral administration of CoQ₁₀ can increase tissue levels, it is possible to correct CoQ₁₀ deficiency and its associated metabolic consequences by supplementation.⁴

Coenzyme Q₁₀ Deficiency

Inherited CoQ₁₀ deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ₁₀ (primary deficiencies) or in genes not directly related to CoQ₁₀ biosynthesis (secondary deficiencies). Respiratory chain defects, reactive oxygen species production, and apoptosis contribute to the pathogenesis of primary CoQ₁₀ deficiencies.^5,⁶

Acquired CoQ₁₀ deficiency is less well established. There are two major factors that lead to deficiency of CoQ₁₀ in humans: reduced biosynthesis, and increased utilization or need by the body. The typical dietary intake of CoQ₁₀ is 3 to 5 mg,⁷ so dietary lack is probably not a significant contributor to CoQ₁₀ deficiency. As mentioned previously, endogenous synthesis is a multistep process that can be affected by aging, disease status, and various medications. Some chronic disease conditions (cancer, heart disease, etc.) are not only associated with reduced biosynthesis, but also increased demand for CoQ₁₀. Measurements of plasma CoQ₁₀ levels have been used to detect deficiencies and are by far the most common clinical assessment of CoQ₁₀ status.⁸ Normal plasma levels are believed to range from 0.45 to 1.5 mcg/mL (or 0.46 to 1.78 µmol/L), with 93% to 100% being the reduced form, ubiquinol.^8,⁹ Some studies used a functional assessment using an assay that measures the citric acid cycle (Krebs cycle) enzyme succinate dehydrogenase-CoQ₁₀ reductase.¹⁰ CoQ₁₀ acts as a critical coenzyme to this enzyme, so if the enzyme is fully saturated with CoQ₁₀ in vivo, addition of exogenous CoQ₁₀ does not increase enzyme activity. Additional methods for assessing CoQ₁₀ status are also becoming available.^5,^11,¹²

Coenzyme Q₁₀ Absorption and Pharmacokinetics

After gastric emptying, CoQ₁₀ is absorbed along with other lipids as chylomicron particles in the small intestine. The primary site of uptake of exogenous CoQ₁₀ is the duodenum, followed by the colon, then the ileum, and then the jejunum. Absorption in the ileum and colon regions supports the possibility of an enterohepatic recirculation of CoQ₁₀. This possibility is further strengthened by the presence of a second peak in plasma levels about 24 hours after administration of either ubiquinone or ubiquinol. Absorption appears to be a complex process involving both active and passive mechanisms.

In the liver, CoQ₁₀ is incorporated with lipoproteins and released into the blood. In plasma, CoQ₁₀ is almost totally associated with lipoproteins, where it has greatest affinity for very low-density lipoprotein (VLDL) and LDL cholesterol. The CoQ₁₀ is then distributed to peripheral tissues for uptake by cells and their mitochondria.

Commercial Forms and Dosage Considerations

Commercially CoQ₁₀ is primarily produced via a yeast fermentation process using Schizosaccharomyces pombe. An alternate source of manufacturing is chemical synthesis using solanesol isolated from the tobacco plant.

A very important consideration in the clinical application of CoQ₁₀ is its pharmacokinetics. CoQ₁₀ as ubiquinone is a crystalline powder that is insoluble in water and has poor absorption characteristics as a result. Ubiquinol has greater solubility and has been promoted as having greater bioavailability that ubiquinone,^4,¹³ but there are limited data currently available and many questions remain to be answered, since ubiquinol is easily oxidized to ubiquinone and absorption studies to date have been suspect. Ubiquinone has an extensive history of use, particularly in oil-based soft-gelatin capsules. Several technologies are now used to enhance the bioavailability of ubiquinone, such as particle size reduction (nanonization) and solubility enhancement via use of emulsifying agents, carriers, and self-emulsifying systems.¹⁴ For example, complexing ubiquinone to a soy peptide (BioQ₁₀ SA) has shown exceptional bioavailability because the soy peptide emulsifies the CoQ₁₀ and helps usher it into the bloodstream.¹⁵ Given the excellent absorption of this form of ubiquinone, the advantage of ubiquinol over regular ubiquinone appears to have more to do with its improved solubility than because it is in the ubiquinol form.

In light of the pharmacokinetic issues, proper clinical dosing is yet to be determined for CoQ₁₀. Therefore, some have suggested that therapeutic targeting will likely be based upon achieving specific plasma CoQ₁₀ levels (e.g., more than 3.5 mg/mL) or tissue saturation.^8,^16,¹⁷ Prescribing a set dosage, even a milligram per kilogram body weight dosage, at this time is a best guess scenario without confirmation by monitoring CoQ₁₀ blood levels, given the differences noted in absorption rates among the different forms as well as the interindividual variability.

Numerous studies have now been conducted claiming enhanced absorption of one form or another.⁴ However, there are shortcomings in most of these studies, and some of the studies appear to have been set up to show an advantage for commercial reasons. For example, ubiquinol is being promoted as the best absorbed form of CoQ₁₀, yet the published studies were set up in a curious fashion. In the one study examining ubiquinol absorption, the administration of the ubiquinol was always with a total of CoQ₁₀ capsules that included the emulsification agents diglycerol monooleate, canola oil, soy lecithin, and beeswax, and although the study utilized a placebo, it did not compare ubiquinol with ubiquinone.¹³ It is possible that ubiquinone might have fared just as well if emulsified as well as the ubiquinol in this study. Absorption studies showed that when CoQ₁₀ was given with food, it was absorbed twice as fast and at least two-fold greater than on an empty stomach.¹⁸ It is believed that food-induced secretion of bile acids is responsible for the improved absorption.

What is known based on current absorption studies is that eventually a steady state is produced (usually after 3 to 4 weeks of constant dosing), and the absorption of CoQ₁₀ may be limited in some individuals. Dosages that exceed an individual’s absorptive capacity for CoQ₁₀ may have minimal effect on efficacy and unnecessarily increase the cost of treatment. When single dosages of CoQ₁₀ begin to exceed 300 mg, the percentage of CoQ₁₀ absorbed declines. Plasma CoQ₁₀ levels at a dosage of 900 mg/day (as ubiquinone in a oil suspension in a soft gel capsule) are not significantly greater than a 600 mg/day dosage. Divided dosages (e.g., two or three times a day) result in higher plasma levels compared with single dosages, especially at higher dosage levels.

Despite the challenges, based upon existing data from published studies, an attempt can be made to calculate the approximate plasma levels of CoQ₁₀ for different commercial forms at 100 and 300 mg doses for at least 30 days with several caveats. First, these are estimates only, based upon a typical 75 kg body weight. Keep in mind that absorption of CoQ₁₀ in any form is likely enhanced considerably if taken with a large meal that includes some fat. Lastly, considerable pharmacokinetic studies in humans have indicated significant interindividual variability in CoQ₁₀ absorption, underscoring the need for monitoring CoQ₁₀ plasma levels during clinical studies and perhaps clinical use of CoQ₁₀ as well (Table 79-1).

TABLE 79-1 Coenzyme Q₁₀ Plasma Levels

DOSE AND FORM	ESTIMATED PLASMA LEVELS IN MICROGRAMs PER MILLILITER
100 mg
Ubiquinone powder in hard gelatin capsule	1.25
Ubiquinone suspended in oil in soft gelatin capsule with rice bran oil	1.8
Ubiquinone solubilized in soft gelatin capsule	2.25
Ubiquinone powder nanonized	2.25
Ubiquinone emulsified with soy peptide in soft or hard gelatin capsule	2.50
Ubiquinol in soft gel capsule	2.50
300 mg
Ubiquinone powder in hard gelatin capsule	2.5
Ubiquinone suspended in oil in soft gelatin capsule with rice bran oil	3.5
Ubiquinone solubilized in soft gelatin capsule	5.0
Ubiquinone powder nanonized	5.0
Ubiquinone emulsified with soy peptide in soft or hard gelatin capsule	7.0
Ubiquinol in soft gel capsule	7.0

The optimal dose of CoQ₁₀ for many clinical indications is not known, and plasma or target tissue levels of CoQ₁₀ are likely the primary determinant of efficacy, rather than the dose.^16,¹⁹ Current opinion based upon the scientific literature is that an acceptable therapeutic plasma target level of CoQ₁₀ should be at least 2.5 mg/mL,²⁰ but levels higher than 3.5 mcg/mL may be necessary for optimum improvement in neurodegenerative diseases and myocardial function.^8,^16,¹⁹ The usual starting dosage for CoQ₁₀ is generally 100 to 200 mg/day. Where possible, the dosage of CoQ₁₀ should be adjusted according to the response of the patient and, preferably, by monitoring plasma CoQ₁₀ levels for 3 to 4 weeks of constant dosing, when steady-state plasma concentrations occur. Less is known about the ability of CoQ₁₀ and the dose required to reach the central nervous system. Again, divided dosages result in higher plasma levels compared with single dosages, e.g., taking 100 mg twice a day produces higher plasma levels compared with taking 200 mg once a day.²¹

Clinical Applications

Given the central role of CoQ₁₀ in mitochondrial function and cellular antioxidant protection, its clinical applications are extensive. There are so many conditions where CoQ₁₀ may offer benefit that there is no question that it should be considered a conditionally essential nutrient. The specific uses of CoQ₁₀ are described in the following:

• General antioxidant

• Cardiovascular disease

• Cardiomyopathy

• Congestive heart failure

• Protection during cardiac surgery

• Parkinson’s disease

• Friedreich’s ataxia

• Muscular dystrophy

• Immune function

• Acquired immunodeficiency syndrome (AIDS)

• Toxicant exposure

• Topical antiaging effects

General Antioxidant

Numerous studies have shown CoQ₁₀ can reduce oxidative damage, DNA strand damage, LDL oxidation, and formation of lipid peroxides, thereby supporting its use as a general antioxidant.^2,²² In particular, CoQ₁₀ is often used to counteract the reduced synthesis of CoQ₁₀ associated with aging. After the age of 35 to 40 years, humans slowly begin to lose their ability to synthesize CoQ₁₀.²³ It has been proposed that the increase in age-associated diseases is due in part to decreased protection afforded by CoQ₁₀ as both an antioxidant and a facilitator of energy production at a cellular level. Therefore, COQ₁₀ is often recommended to counteract this effect.

For example, recent studies identified oxidative stress as a promoting factor for dry mouth (xerostomia) and the development of Sjögren’s syndrome, a condition associated with significant dry mouth. Basically, oxidative damage leads to the inability of salivary cells to produce enough ATP to secrete sufficient amounts of water. CoQ₁₀ exerts antioxidant effects, but its main action in relieving dry mouth may be by increasing energy (ATP) production, allowing the saliva producing cells enough energy to secrete more saliva into the mouth. In one double-blind study, 66 patients, including 31 with dry mouth, were given either ubiquinol or ubiquinone orally at a dosage of 100 mg/day, or a placebo for 1 month.²⁴ Salivary secretion and salivary CoQ₁₀ content were analyzed before and after treatment. Among the dry mouth patients treated with ubiquinone, salivary secretion increased significantly from 0.7 g/2 min before treatment to 1.2 g/2 min after 1 month of treatment. Among the patients treated with ubiquinol, salivary secretion also increased significantly from 0.8 g/2 min before treatment to 1.4 g/2 min after treatment. In normal subjects without dry mouth, salivary secretion increased with ubiquinone (from 4.9 to 5.7 g/2 min) at a statistically significant level, but did not differ significantly after treatment with ubiquinol (from 3.5 to 3.8 g/2 min). Either form of CoQ₁₀ exhibited a marked increase in salivary CoQ₁₀ concentration (ubiquinol more than ubiquionine in dry mouth, ubiquinone more than ubiquinol in normal subjects), suggesting that the observed increase in salivary secretion was attributable to the effect on salivary levels of CoQ₁₀.

Cardiovascular Disease—General Considerations

Enhancing myocardial function is an important, although frequently overlooked, component of the overall prevention and treatment of cardiovascular disease. CoQ₁₀ plays a key role in energy production and is therefore essential for all energy-dependent processes, including heart muscle contraction. CoQ₁₀ deficiency has been documented in patients with various types of cardiovascular disease. Whether a decline in CoQ₁₀ levels is a cause or a consequence of heart disease is unclear. Cardiac cells are highly metabolically active, and thus have higher mitochondrial coenzyme requirements to maintain ATP production. In addition to its role in cellular energetics, exogenously administered CoQ₁₀ acts as an antioxidant to inhibit LDL oxidation,²⁵ decreases proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and attenuates markers of oxidative and nitrative stress in a dose-dependent manner.²

CoQ₁₀ deficiency is common in patients with various types of cardiovascular disease.^2,²⁶ Approximately 75% of patients who had cardiac surgery were shown to be deficient in myocardial CoQ₁₀. Concentrations of CoQ₁₀ declined progressively in both blood and myocardial tissue with increasing severity of heart disease.²⁷ Myocardial deficiencies of CoQ₁₀ were also found in the majority of patients with aortic stenosis or insufficiency, mitral stenosis or insufficiency, diabetic cardiomyopathy, tetralogy of Fallot, atrial septal defects, and ventricular septal defects.²⁸

Cardiomyopathy

Cardiomyopathy can take several forms, but all are manifested by weakening of the heart muscle associated with inadequate heart pumping or other functional problems. The well-established role of CoQ₁₀ as a facilitator of mitochondrial energy production lends strong rationale for a role of CoQ₁₀ supplementation in all forms of cardiomyopathy.

A prospective, randomized, double-blind, placebo-controlled trial was conducted in 38 children with idiopathic dilated cardiomyopathy. After 6 months of supplementation, there was a statistically significant (P = 0.011) improvement in diastolic function, leading the authors to conclude that “administration of coenzyme Q₁₀ is useful in ameliorating cardiac failure in patients with idiopathic dilated cardiomyopathy.”²⁹

In one study, 126 patients with dilated cardiomyopathy received 100 mg/day of CoQ₁₀ for up to 66 months. After 6 months of treatment, the mean left ventricular ejection fraction (LVEF) increased from 41% to 59% (P <0.001) and remained stable thereafter with continued treatment. After 2 years, 84% of the patients were still alive, and at 5.5 years, 52% were alive.³⁰ These survival rates were considerably better than the published survival statistics of patients given conventional therapy (i.e., 2-year survival rate of 50% for symptomatic cardiomyopathy, and 1-year survival rate of 50% for decompensated cardiomyopathy).

In another study, 88 patients with cardiomyopathy received 100 mg/day of CoQ₁₀ for 1 to 24 months. Significant improvements in at least two of three cardiac parameters (LVEF, cardiac output, and New York Heart Association [NYHA] class) were seen in 75% to 85% of the patients. Approximately 80% of the patients improved to a lower (i.e., more favorable) NYHA functional class.²⁰

In a double-blind, crossover trial, 19 patients with cardiomyopathy received 100 mg/day of CoQ₁₀ or a placebo, each for 12 weeks. Compared with placebo, CoQ₁₀ treatment significantly increased cardiac stroke volume and LVEF. Eighteen patients reported improvement in activity while taking CoQ₁₀.³¹

Congestive Heart Failure

The potential of CoQ₁₀ as a treatment for congestive heart failure (CHF) was suggested as early as 1967 by Japanese researchers.³² In 1976, these same investigators administered 30 mg/day of CoQ₁₀ to 17 patients with CHF. All of the patients improved, and nine (53%) became asymptomatic after 4 weeks of treatment.³³ Numerous studies since have demonstrated that CoQ₁₀ supplementation resulted in an improvement of stroke volume, LVEF, cardiac output, cardiac index and end-diastolic volume index.^2,^34,³⁵

In the largest multicenter trial completed to date, 2664 patients in NYHA classes II and III CHF received 50 to 150 mg/day of CoQ₁₀ (78% of patients received 100 mg/day of CoQ₁₀). After 3 months of supplementation, the results showed a low incidence of side effects, and the following proportion of patients had improvements in clinical signs and symptoms ³⁶: