L-Arginine and L-Citrulline, Better Together

L-Arginine and L-Citrulline, Better Together


L-Arginine is a semi-essential amino acid, meaning the body usually produces enough of it on its own, but supplementation can be beneficial. L-arginine is also a precursor to nitric oxide. A significant part of L-arginine metabolism occurs in the liver. It is a critical component of the urea cycle, where it is converted into urea and ornithine. The urea is then excreted by the kidneys, and ornithine can be used to generate more citrulline and arginine, thus continuing the cycle.

L-Citrulline is a non-essential amino acid, which means the body can produce it on its own. L-citrulline is converted into L-arginine in the body, and like L-arginine, it is involved in the production of nitric oxide. It is also known for reducing fatigue and improving endurance in both aerobic and anaerobic exercises. L-citrulline plays a unique role in the body, particularly in the kidneys. After being produced in the liver as part of the urea cycle, citrulline travels to the kidneys. In the kidneys, citrulline is converted back into L-arginine, which can then be utilized for nitric oxide synthesis or re-enter the bloodstream. This conversion in the kidneys makes citrulline an effective means of increasing arginine levels in the body.

L-Arginine and L-Citrulline in the Urea Cycle

Nitric Oxide is a molecule that plays a role in various bodily processes. It is a vasodilator, meaning it relaxes the inner muscles of the blood vessels, causing them to widen and increase circulation. This can be beneficial for exercise performance in several ways, including improved blood flow, reduction in blood pressure, enhanced exercise performance, and faster recovery.

L-Arginine and L-Citrulline are both considered to be nitric oxide boosters. However, arginine is responsible for the actual production of NO (nitric oxide). L-Citrulline is an amino acid that has benefits such as reducing fatigue and improving endurance in both aerobic and anaerobic exercises. L-Citrulline is metabolized and converted to arginine in the kidneys instead of the liver and has shown to increase the bioavailability of arginine in the blood more effectively than taking L-arginine on its own. L-Arginine, in contrast, is first metabolized in the liver where some is lost in the chemical breakdown of the molecule. L-Citrulline has been shown to be more effective in raising arginine levels due to its ability to bypass liver metabolism.

Benefits of L-Arginine and L-Citrulline

L-Arginine and L-Citrulline are both NO boosters that are interconverted in the urea cycle. The urea cycle is a biochemical pathway in the body that converts toxic ammonia into urea, which is then excreted in urine. Conversion of Citrulline to Arginine (Primarily in the Kidneys): Citrulline, produced in the liver as a part of the urea cycle, travels to the kidneys. In the kidneys, citrulline undergoes a two-step enzymatic process to become arginine. The first step involves the enzyme argininosuccinate synthetase, which combines citrulline with aspartate to form argininosuccinate, using ATP as an energy source. The second step is catalyzed by the enzyme argininosuccinate lyase, which splits argininosuccinate into arginine and fumarate.

Conversion of Arginine to Citrulline (Primarily in the Liver): Arginine is a precursor for the production of NO, a vital signaling molecule in the body. The conversion of arginine to citrulline occurs during the synthesis of NO. This process is catalyzed by the enzyme nitric oxide synthase (NOS). As NOS catalyzes the production of NO, arginine is oxidized, resulting in citrulline and NO as byproducts. The citrulline produced can then re-enter the urea cycle, primarily in the liver, or be transported back to the kidneys for reconversion to arginine.

Mechanism of Action

Although L-Arginine and L-Citrulline are different molecules, they are both needed for the urea cycle and are constantly converted from one to the other in biochemical reactions that produce NO and other byproducts essential for various physiological processes.

Combined Effects on Arginase Levels

Arginase is an enzyme that is essential for the urea cycle and arginine metabolism. Its primary function is to help detoxify ammonia in the liver and to regulate arginine availability in various tissues. Taking L-Arginine and L-Citrulline together does not increase arginase levels any more so than taking L-Arginine or L-Citrulline alone. Moreover, the combination of the two amino acids has shown to inhibit the production of arginase, resulting in higher NO and arginine levels in the blood. As stated in the journal of Bioscience, Biotechnology, and Biochemistry, "the combination group showed the highest mean value. Taken together, L-citrulline appears to work as an inhibitor of arginase and precursor of L-arginine: as a result, plasma L-arginine synergistically increases when it is simultaneously supplemented with L-arginine" (Takashi, 2017).

Why Combine L-Arginine and L-Citrulline?

Taking L-citrulline and L-arginine together is more effective than taking either amino acid alone due to their complementary roles in NO synthesis and their unique absorption and metabolic pathways. Here are a few key reasons why their combined supplementation is better than taking one or the other: Using both sustains and enhances the production of nitric oxide over a longer period of time. By combining L-citrulline and L-arginine, you maximize the availability of arginine for nitric oxide production. L-citrulline extends the effectiveness of L-arginine by continuously replenishing the L-arginine supply in the blood. The combination offers synergistic effects, as each amino acid enhances the action of the other. The combination of the two inhibits the production of arginase, the enzyme that metabolizes arginine in the blood.


  • Masahiko Morita, Toshio Hayashi, Masayuki Ochiai, "Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability," Biochemical and Biophysical Research Communications, Volume 454, Issue 1, 2014, Pages 53-57, ISSN 0006-291X, https://doi.org/10.1016/j.bbrc.2014.10.029
  • Rachel Botchlett, John M. Lawler, Guoyao Wu, "Chapter 55 - l-Arginine and l-Citrulline in Sports Nutrition and Health," Nutrition and Enhanced Sports Performance (Second Edition), Academic Press, 2019, Pages 645-652, ISBN 9780128139226, https://doi.org/10.1016/B978-0-12-813922-6.00055-2
  • Takashi Suzuki, Masahiko Morita, Toshio Hayashi, Ayako Kamimura, "The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males," Bioscience, Biotechnology, and Biochemistry, Volume 81, Issue 2, 1 February 2017, Pages 372–375, https://doi.org/10.1080/09168451.2016.1230007
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