L-citrulline is an alpha-amino acid that is present in all mammals, including humans, in plants, and, in fact, in small amounts in almost every living organism. One of the richest plant sources of L-citrulline is watermelon (Citrullus vulgaris Schrader), from which the amino acid was first isolated and from which its name is derived. L-citrulline is also present at high levels in other members of the cucurbitaceae family, including cucumbers, pumpkins, muskmelons, bitter melons, squashes, gourds, dishrag gourds, wax gourds, honeydews, cantaloupes and luffas. It is also found in high concentration in young walnut seedlings, and in negligible amounts in the kernels and sap of Japanese white birch. L-citrulline can also be obtained via tryptic digestion of casein.
L-citrulline is classified as a nonessential amino acid, which is defined as an amino acid that the body can synthesize in sufficient quantities for all its biochemical and physiological needs. There are, however, conditions in which the body cannot manufacture an adequate amount. L-citrulline is then required in the diet. One such condition is short bowel syndrome. The gut is the main site of L-citrulline production in the body. Short bowel syndrome is a malabsorption disorder caused by the surgical resection of the small intestine. Thus, the main site of L-citrulline production is greatly diminished, and, as a consequence of reduced plasma L-citrulline levels, plasma L-arginine levels are also reduced (L-citrulline is the major precursor of L-arginine). In this condition, both L-citrulline and L-arginine become essential amino acids and must be supplied in the diet. In that regard, L-citrulline and L-arginine are better thought of as conditionally essential or semi-essential amino acids.
There are other conditions where dietary L-citrulline needs to be supplied. L-citrulline is a key intermediate in the urea cycle. A human being is a ureotelic organism, meaning that humans excrete excess nitrogen in the form of urea and do so via the urea cycle, a metabolic cycle which is operative in the liver and composed of five biochemical steps. Certain genetic inborn errors of urea metabolism exist in which either excessive amounts of L-citrulline are produced or very small amounts of L-citrulline are produced. In either case, rather than urea being produced, excess amounts of ammonia are produced. This can be handled just fine by an ammonotelic bony fish but can be life-threatening for humans. Fortunately, the inborn errors of metabolism of the urea cycle are rare. The first step in the urea cycle is the reaction of ammonia and bicarbonate fueled by adenosine triphosphate (ATP) and catalyzed by the enzyme carbamoyl phosphate synthetase (CPS) to produce carbamoyl phosphate. The second metabolic step of the cycle is the reaction of carbamoyl phosphate and L-ornithine to produce L-citrulline, catalyzed by the enzyme ornithine transcarbamylase (OTC). Deficiencies of either of these two enzymes lead to low serum levels of L-citrulline and are treated with oral L-citrulline.
L-citrulline is also classified as a nonprotein amino acid. What this means is that L-citrulline cannot be incorporated into proteins during the process of translation, which is the transfer of genetic information into proteins. Each protein amino acid has its own trinucleotide codon. L-citrulline does not have its own trinucleotide codon. However, L-citrulline is found in some proteins; when this occurs, it is due to a post-translational modification of those proteins. The proteins so modified are called citrullinated proteins.
It is only relatively recently that L-citrulline has raised interest in the scientific community. For years, it was thought of as just an intermediate in the urea cycle. However, that began to change in the 1980s when it was demonstrated that there is a continuous release of L-citrulline from the small intestine into the circulation, which is mainly taken up by the kidneys and metabolized into L-arginine (See L-Arginine). With the discovery of L-arginine's role as a precursor in the production of nitric oxide (NO) and the importance of NO in the cardiovascular system, the nervous system and the immune system, the close link between L-citrulline and L-arginine has raised considerable interest in the scientific community. Most recently, there is some evidence that this nonprotein amino acid may play a major role in the regulation of protein synthesis.
The empirical formula of L-citrulline is C6H13N3O3, and its molecular weight is 175.19. It is described chemically as 2-amino-5-(carbamoylamino) pentanoic acid, and its CAS Registry number is 372-75-8. L-citrulline is also known as citrulline, N5-(aminocarbonyl)-L ornithine, delta-ureidonorvaline, alpha-amino-delta-ureidovaleric acid and by the three letter abbreviation CIT. L-citrulline is very soluble in water. Although L-citrulline is an L-amino acid, it is usually referred to as just citrulline. L-citrulline is represented by the following chemical structure.
Actions & Pharmacology
L-citrulline has antioxidant activity. It may have antihypertensive activity and, under certain conditions, it has putative anabolic activity.
Mechanism of Action
Antioxidant activity: L-citrulline operates as a secondary metabolite in some plants. Secondary metabolites protect plants against various stress situations. One interesting activity that L-citrulline possesses is the protection of watermelons, specifically watermelon leaves, against the ravages of drought conditions.
Plants are susceptible to stress and injury from pests, fungi and weeds. Drought is one of the major abiotic stresses affecting plant productivity. Under drought conditions, the generation and proliferation of reactive oxygen species, including hydroxyl radicals, increases and results in oxidative damage to plant cells, affecting their nucleic acids, proteins, carbohydrates and lipids. Plant cells have a number of antioxidant defense mechanisms against oxidative stress, including small antioxidant molecules and antioxidant enzymes. However, under drought conditions, the stress of the drought may overwhelm all of those defense mechanisms.
It is noteworthy that wild watermelon plants that inhabit the Kalahari Desert in Botswana exhibit very high drought tolerance. Even when exposed to prolonged drought in strong sunlight, the photosynthetic apparatus of the plants remains intact. It turns out that drought stress induces massive accumulation of L-citrulline in the watermelon leaves. Even the regular watermelon that we eat has been found to possess significant amounts of L-citrulline in its flesh and rind. In fact, the explorer David Livingston thought that watermelon originated in the Kalahari Desert. However, the concentrations of L-citrulline in the Kalahari watermelons and watermelon leaves are much higher than they are in the watermelons that we eat. Studies have shown L-citrulline to be an extremely potent scavenger—arguably the most potent scavenger—of hydroxyl radicals and it has been demonstrated to protect DNA and metabolic enzymes against oxidative stress. The exact mechanism of L-citrulline's protective effect against oxidative stress and the various chemical reactions that take place between L-citrulline and hydroxyl radicals need further study. Interestingly, L-arginine itself appears to have some detrimental effects in the watermelon, and it is thought that the wild watermelon plant has evolved regulatory mechanisms for accumulating L-citrulline preferentially rather than L-arginine. On the other hand, it has been found that watermelon consumption increases plasma L-arginine concentration in adults, and that appears to be a good thing.
Antihypertensive activity: The vascular endothelial bioavailability of nitric oxide (NO) is the major factor in the regulation of vascular tone. Normal blood pressure requires a relaxed vascular tone. When the bioavailability of endothelial NO decreases, for example when the blood vessel is under oxidative stress, the result is blood vessel constriction, which leads to hypertension. The signaling molecule NO regulates vascular tone by increasing intracellular cGMP (cyclic-guanosine monophosphate), which activates cGMP-dependent protein kinase 1 (PKG1).
As discussed above, L-arginine is the precursor of NO, including endothelial NO (eNO). One might speculate that increasing L-arginine in the body would yield increased amounts of NO, including eNO, which would lead to blood vessel relaxation and decreased blood pressure. Supplemental L-arginine has been used in a number of studies to improve eNO-mediated vasodilation. The results have been generally disappointing, and it is thought that, in part, this is because of the catabolism of L-arginine in the liver and the small intestine via arginase enzymes. In contrast, supplemental L-citrulline is readily absorbed, is not catabolized in either the liver or the small intestine and winds up being converted to L-arginine.
A recent study looked at the effect of supplemental L-citrulline on the production of L-arginine, urinary cGMP and nitrate excretion rates (measures for cGMP and NO production), the ratio of plasma L-arginine over asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (L-arginine/ADMA ratio), pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) and flow-mediated vasodilation (FMD). The study was a double-blind, randomized, placebo-controlled cross-over study with 20 healthy, normotensive subjects who received six different dosing regimes of placebo, L-citrulline and L-arginine. The study lasted seven days. This study wasn't meant to determine if L-citrulline has antitensive activity, but to establish a model for a study that might give us that answer.
The results of the study were as follows: L-citrulline dose-dependently increased AUC (area under the curve) and Cmax (maximum concentration) of plasma L-arginine more effectively than L-arginine. The highest dose of L-citrulline (3 grams twice a day) increased the Cmin (minimum concentration) of plasma L-arginine and significantly improved the L-arginine/ADMA ratio, indicating decreased inhibition of NOS—a good thing. Further, urinary cGMP and urinary nitrate both were significantly increased—also a good thing. However, the FMD data showed no difference from baseline with any treatment—not such a good thing. However, pooled analysis of all FMD data revealed a correlation between the increase of L-arginine/ADMA ratio and improvement of FMD—better than nothing. The authors of the study concluded that supplemental L-citrulline raises plasma L-arginine concentration and augments NO-dependent signaling in a dose-dependent manner. Not much more can be concluded from this study. The volunteers were healthy and normotensive. Larger prospective clinical studies with longer treatment periods to investigate the effects of supplemental L-citrulline on endothelial function in those with endothelial dysfunction and vascular disease (including hypertension, hypercholesterolemia, coronary artery disease and peripheral artery disease) are necessary and warranted.
The spontaneous hypertensive rat (SHR) is an animal model for essential hypertension. As discussed above, the vascular bioavailability of endothelial nitric oxide (eNO) is the major determinant of vascular tone and blood pressure. Low eNO vascular bioavailability is associated with vascular constriction and the development of hypertension. It was found that low levels of NO in the kidneys of female SHRs during nephrogenesis precede hypertension in the animals (prehypertension). In these female offspring, the gene expression of arginosuccinate synthase, which is involved in renal L- arginine synthesis and the gene expression of the renal cationic amino acid Y-transporter, which is involved in L-arginine reabsorption, were both decreased in 2-day and 2-week SHRs compared with normotensive control rats. In addition, 2-week-old female SHRs had much less NO in their kidneys but not in their hearts. Maternal supplementation with L-citrulline was found to increase renal NO in the female pup SHRs at 2 weeks and persistently ameliorated the development of hypertension. In the male pup SHR offspring, hypertension developed at 20 weeks. The mechanism of action of the antihypertensive effects of L-citrulline is not clear.
Anabolic activity (putative): There are a number of studies showing that under certain conditions, dietary L-citrulline may have protein anabolic activity. L-citrulline was demonstrated to modulate muscle protein metabolism in old malnourished rats. Protein energy malnutrition is not uncommon in the elderly, particularly those who have poor or no support from family and/or friends. One hypothesis is that the poor response to nutrition with advancing age might be related to splanchnic sequestration of amino acids, meaning that fewer amino acids reach the systemic circulation. L-citrulline, unlike L-arginine, is not taken up and metabolized by the liver and may offer a means to increase nitrogen balance and improve nutritional status. In a study of old malnourished rats, it was found that L-citrulline supplementation led to higher protein synthesis overall and higher protein content in the muscles. A standard diet did not have any effect on protein synthesis or on protein content in the muscles. The exact mechanism of this possible anabolic effect is unclear.
In another study, a group of rats underwent massive intestinal resection. L-citrulline was found to increase L-arginine levels and improve nitrogen balance in these animals. The fact that L-citrulline is not taken up and metabolized by the liver may also have something to do with restoring nitrogen balance in this situation.
In these two different situations—old malnourished rats and rats having undergone massive intestinal resection—L-citrulline was found to have a dramatic effect on nitrogen balance and protein status. Recently, it has been found that L-citrulline may also stimulate muscle protein synthesis. The mechanism of action of this effect is unclear, but there are some thoughts about it—the effect may be due to L-citrulline's ability to generate L-arginine or to stimulate insulin and/or growth hormone secretion, or L-citrulline may be a vehicle to bring nitrogen to the muscles. The last two possibilities would be indirect actions of L-citrulline. However, L-citrulline may have direct action in stimulating protein synthesis in muscles. Some recent studies appear to suggest the possibility of direct action. If that is indeed the case, L-citrulline may play a major role in protein homeostasis. Are there any examples of amino acids that can directly stimulate protein synthesis and that may even possess signaling activities? L-leucine is the one that comes to mind and, interestingly, neither L-leucine nor L-citrulline is metabolized in the liver. Much research in this important area is needed and certainly warranted.
This section on the pharmacokinetics (PK) of L-citrulline begins with the various biochemical reactions that L-citrulline participates in either as reactant or product.
L-citrulline from L-arginine via nitric oxide synthase:
The nitric oxide synthase (NOS) reaction converts L-arginine to NO and L-citrulline. The reaction has L-arginine, NADPH and oxygen as reactants and NO, L-citrulline and NADP as products. There are three forms (isoforms) of nitric oxide synthase—a neuronal type called nNOS, an endothelial type called eNOS and an inducible form called iNOS.
L-citrulline formation in the enterocytes of the small intestine from L-glutamine and L-arginine:
The small intestine is the main source of L-citrulline production in humans and the major precursor of L-citrulline is the amino acid L-glutamine. Nearly 90% of the circulating L-citrulline arises from L-glutamine. The contribution of L-arginine to L-citrulline synthesis accounts for approximately 10% of the circulating L-citrulline. L-glutamine is converted to L-glutamate via glutaminase. L-glutamate is converted to L-ornithine via ornithine aminotransferase. L-ornithine is converted to L-citrulline via ornithine carbamoyltransferase. L-citrulline is transported to the kidneys where it is converted to L-arginine via arginosuccinate synthase and arginosuccinate lyase.
L-citrulline can also be synthesized in the small intestine from L-arginine because the enterocytes possess the two enzymes—arginase II and ornithine carbamoyl transferase—needed for L-citrulline synthesis. However, the activity of the two enzymes that catabolize L-citrulline—arginosuccinate synthase and arginosuccinate lyase—is very low in the small intestine. Therefore, L-citrulline cannot be used in situ (the small intestine) to produce L-arginine and is released as such into the circulation. Importantly, L-citrulline is not taken up by the liver, but is mainly taken up by the kidneys. Since the kidney possesses arginosuccinate synthase and arginosuccinate lyase activity but not the other enzymes of the urea cycle, L-arginine is released, and 75% of L-citrulline produced in the small intestine is taken up by the kidneys, where it is converted into L-arginine. The intestinal synthesis rate of L-citrulline formation is the crucial regulatory event in renal L-arginine synthesis. The arginine-citrulline-arginine interorgan cycle can be seen as a means to protect dietary L-arginine from excessive liver degradation, since L-arginine is catabolized in the liver by arginase, and to correctly adapt the rate of urea formation according to protein intake, since L-arginine is a major positive urea formation regulator. (L-arginine is the activator of N-acetylglutamate, which in turn activates carbamoyl phosphate synthetase). L-glutamine is the second major substrate regulating the rate of urea formation; the ammonia derived from L-glutamine metabolism upregulates liver glutaminase. L-citrulline may be seen as a means to sustain protein homeostasis, particularly when the intake of protein is low. In the condition of low protein intake, ornithine carbamoyltranferase expression in the liver increases, thus promoting the formation of L-citrulline and thereby allowing the downregulation of the formation of urea in the liver.
L-citrulline formation in the urea cycle (in the liver):
The liver and the small intestine are the two organs that play a major role in the metabolism of L-arginine. Since the activity of arginase is very high in the liver, most of the L-arginine that reaches the liver is converted into urea.
The urea cycle, also known as the Krebs-Henseleit cycle, is operative in the liver and consists of five reactions—two in the mitochondria and three in the cytosol. The major role of the urea cycle is the detoxification of ammonia, the end product of nitrogen metabolism. Bony fish can excrete ammonia directly, but humans need to convert ammonia to urea. The first step in the urea cycle is the conversion of ammonia and carbon dioxide to carbamoyl phosphate catalyzed by the enzyme carbamoyl phosphate synthetase. Carbamoyl phosphate then reacts with L-ornithine to produce L-citrulline catalyzed by the enzyme ornithine transcarbamoylase. The first two reactions take place in the mitochondria; the remaining three in the cytosol. L-citrulline then reacts with aspartate to form arginosuccinate catalyzed by the enzyme arginosuccinate synthase. Arginosuccinate is then converted to L-arginine and fumarate, catalyzed by the enzyme arginosuccinase, and, finally, L-arginine is converted to L-ornithine and urea, catalyzed by the enzyme arginase. The cycle continues.
It is clear from all of these reactions that the biochemistry of L-arginine is very closely tied to the biochemistry of L-citrulline. It also appears that L-arginine may not be the best supplement form of L-arginine since it gets broken down in the liver via the enzyme arginase and also a fairly large proportion of dietary L-arginine is extracted during a first-pass splanchnic extraction and degraded by the intestine via the enzyme arginase to yield L-ornithine and L-proline. Could L-citrulline be a better delivery form of L-arginine than L-arginine itself? The Pharmacokinetics (PK) of L-citrulline that follows addresses this.
Pharmacokinetics of L-citrulline:
The PK of L-citrulline in humans is not complete, but much is known. Following ingestion, L-citrulline is absorbed from the lumen of the small intestine into the enterocytes. Rat studies and studies in Caco-2 cells, a model of human enterocytes, have demonstrated that L-citrulline absorption involves a sodium-dependent active transport mechanism. Absorption of L-citrulline appears to be efficient. L-citrulline is released from the enterocytes into the circulation, and approximately 83% of the circulating L-citrulline is taken up by the kidneys where most of it is converted to L-arginine via arginosuccinate synthase and arginosuccinate lyase. This occurs in the cells of the proximal tubules of the kidneys. In contrast to L-arginine, L-citrulline bypasses first-pass splanchnic extraction and reaches the kidneys completely intact. The L-arginine produced from L-citrulline and L-citrulline itself are absorbed and reabsorbed, respectively, by the renal tubules. Less than 1% of an oral dose of L-citrulline is excreted in urine.
L-arginine released in the bloodstream is distributed to the various tissues of the body where it can be utilized for protein synthesis, urea synthesis, NO production and other biochemical reactions. (See L-Arginine.) Interestingly and importantly, some studies have shown that the Cmax (maximum concentration in the plasma) of L-arginine when subjects are administered L-citrulline is significantly higher than the Cmax of L-arginine when subjects are given an equivalent dose of supplemental L-arginine. As mentioned above, L-arginine undergoes significant catabolism in the liver via arginase, and in the small intestine, again, via arginase. Supplemental L-citrulline is neither catabolized in the liver nor in the small intestine, remaining chemically intact. Thus, it turns out that supplemental L-citrulline appears to be a better delivery form of L-arginine than is L-arginine itself. It may also be concluded that oral L-citrulline can be used to enhance the availability of L-citrulline and L-arginine in the systemic bloodstream, without enhancing urea excretion, and thus may improve nitrogen balance in vivo in humans.
Indications & Usage
L-citrulline, a nonprotein amino acid precursor of L-arginine, may be helpful in treating/preventing hypertension, metabolic syndrome and cardiovascular disease, generally. It may also be useful in sustaining/improving protein metabolism in some intestinal diseases, such as short-bowel syndrome. It has long been used to treat some inherited urea cycle disorders. Some consider it a safer way of utilizing L-arginine, a conditionally essential amino acid, and that it might thus serve as a substitute supplement in disorders related to L-arginine deficiency. There is no convincing evidence to support the claim that L-citrulline may enhance athletic performance or be helpful in erectile dysfunction. It may, however, play some positive role in muscle protein metabolism. The suggestion that it might be effective in some autoimmune disorders, such as rheumatoid arthritis, psoriasis and multiple sclerosis remains entirely hypothetical.
L-citrulline dietary supplements are available. A typical dose is three grams a day. Optimal doses are not known.
Watermelon is a rich source of L-citrulline.
L-citrulline concentrations in seeded watermelons range from 0.5 to 3.6 mg per gram fresh weight, with an average of 1.8 mg per gram fresh weight.
L-citrulline concentrations in seedless watermelons range from 0.7 to 3.5 mg per gram fresh weight with an average of 2.4 mg per gram fresh weight.
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Research & Summary
L-citrulline is found only in very small amounts in most foods. One rich source of it, however, is watermelon, and watermelon feeding studies (in animals) have shown that three cups of watermelon juice daily can boost plasma L-arginine levels by 12 per cent and six cups daily can boost those levels by 22 percent. (One would expect variations in this result, however, depending upon the strain and relative maturity of the watermelons used.) The prospect of using L-citrulline to boost L-arginine levels in the body has excited attention recently because, unlike L-arginine itself, L-citrulline is not taken up and largely metabolized by the liver, a process that yields urea. Thus it may be a safer vehicle for boosting L-arginine in the body than through the use of L-arginine itself.
The importance of this is considerable since L-arginine's essentiality is well established in some circumstances: in mammals, including humans; in infants; in adults with burns and other trauma; in individuals with renal failure; and in those with massive small bowel resection, as well as some other disorders of the gut. One group of researchers has recently concluded that L-citrulline should now be viewed as a potential, safer approach to providing oral, enteral and parenteral nutrition in gut-compromised patients.
An L-citrulline-rich diet has significantly combated protein-energy malnutrition in a rat model of short bowel-syndrome. This is to be expected since the primary site of L-citrulline production in the body is significantly reduced in massive intestinal resection. Short-bowel syndrome leaves the body short of this amino acid and thus of its frequently essential descendant, L-arginine. Some other animal studies suggest that L-citrulline may have some protein anabolic effect. In one study of old, undernourished rats, supplementation with the amino acid improved nitrogen balance and muscle protein synthesis. Whether this effect can be found in older human, undernourished and malnourished patients needs to be investigated. The mechanism by which this amino acid may aid nutrition could equally apply in some cases of nutritive deficit related to cancer, type 2 diabetes, trauma and some other diseases/disorders.
The idea that L-citrulline might be useful as an athletic performance enhancer was not confirmed in a study of young male and female volunteers subjected to incremental treadmill challenges. Test subjects were given three to nine grams of the substance prior to testing and compared with placebo controls. Contrary to expectations there was actually a reduction in time to exhaustion among those taking the amino acid during a 24-hour period prior to challenge. This was a small study from which no meaningful conclusions can be drawn.
At least as significant as its potential role in the gut is the potential for L-citrulline to be of benefit in cardiovascular health. The recycling of L-citrulline to L-arginine plays a crucial role in the production of nitric oxide (NO) in endothelial cells. As a vital vasorelaxant, NO production is of importance in maintaining cardiovascular health. Impaired NO production results in the endothelial dysfunction that is associated with atherosclerosis, lipid disorders, hypertension, diabetes and other indicators of heart disease and the metabolic syndrome. Once again, because of problems inherent in L-arginine availability and safety in the body, L-citrulline is viewed as the better way to treat conditions associated with L-arginine deficiencies.
L-citrulline was found to inhibit the progression of atherosclerosis experimentally induced via a high-cholesterol diet in rabbits. The researchers concluded that the amino acid achieved this result through antioxidative and NO-boosting actions. The regression of lesions in these animals given the amino acid orally for 12 weeks was said to be dramatic. In another animal study, maternal supplementation with L-citrulline increased renal nitric oxide and exerted long-lasting antihypertensive effects in young, spontaneously hypertensive rats. The rat dams were supplemented with the amino acid during pregnancy and lactation. The antihypertensive effects observed persisted in the offspring for several weeks. In yet another animal study, the metabolic syndrome was significantly ameliorated in an animal model of noninsulin-dependent diabetes mellitus (the Zucker diabetic fatty rat). Supplementation was in the form of watermelon juice, which the authors suggested may be a useful functional food. Reduced serum concentration of cardiovascular risk factors and improved glycemic control were noted in this study. Clearly research in this context needs to be extended into the clinical domain.
There is some very preliminary evidence that L-citrulline may have immunomodulating effects that could be favorable, possibly through enhancement of T-lymphocytes. Enhanced NO production by macrophages should, additionally, it is suggested, help resist a number of infectious agents. A role in autoimmune disorders has also been proposed, possibly mediated through the amino acid's presence in myelin protein, but this remains hypothetical.
Recently, watermelon was touted in the press as a possible ""natural Viagra.'' Other researchers, however, cast doubt on the idea that eating watermelon, even in very large quantities, would be sufficient to have any meaningful impact on erectile dysfunction.
Contraindications, Precautions & Adverse Reactions
Supplemental L-citrulline is contraindicated in those hypersensitive to any component of an L-citrulline-containing dietary supplement.
The use of L-citrulline supplements for any health condition should be discussed with ones physician.
Because of an absence of long-term safety studies, pregnant women and nursing mothers should avoid L-citrulline supplements. There is no precaution for eating foods containing L-citrulline, including watermelon.
Oral supplementation with L-citrulline at doses up to 15 grams daily is generally well tolerated. Gastrointestinal symptoms, including diarrhea, might be expected with very high doses.
No known interactions.
No known interactions.
No known interactions.
No known interactions.