# L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
## 4 Pharmacokinetics and Pharmacodynamics of L-Citrulline  
The characteristics of the pharmacokinetic parameters of CIT resemble those of related amino acids, Arg and ornithine, but not Cmax (peak concentration) which is several times greater in CIT than in Arg or ornithine [40]. Therefore, unlike Arg, the intestine or liver do not metabolize CIT; it is not a substrate for the arginase enzymes because CIT bypasses splanchnic extraction [18] and also inhibits its activity [41]. This could explain why plasma Arg levels rise rapidly and significantly when administered together, giving rise to the suggestion that Arg could pass through the gastrointestinal tract and liver without suffering the influence of intestinal and hepatic-first pass effects, which is likely to be due to CIT inhibiting aginase activity [30]. Oral CIT administration can be used to enhance systemic CIT and Arg availability; it is bioavailable and losses in urine are very low [42]. In a combined sample of middle-aged women and men, [PERSON] et al. [43] found that oral CIT supplementation, at a dose of 1.5 g twice daily for one week, increased the plasma concentrations of CIT and Arg in a dose-dependent manner and augmented plasma Arg levels with greater effectiveness than by supplementing Arg in healthy subjects. [PERSON] et al. [44] found a similar behavior in healthy elderly subjects when a single dosing caused a marked increase in Arg availability when CIT (10 g) was administered, compared with Arg (9.94 g) administration itself. Previously, in a study performed in healthy men, using oral loads (2, 5, 10, or 15 g CIT) administered at random, [PERSON] et al. [40], had found that the plasma CIT concentration increased rapidly and massively (10-fold at the 2 g load to 100-fold at the 15 g load) and returned to baseline values within 5-8 h post-loading. These authors demonstrated that CIT was well tolerated (no side effects) and did not induce gastrointestinal disorders at a high dose (i.e., 15 g), thus suggesting that intestinal absorption of CIT is not a limiting step. However, Arg production was lower than expected when 15 g of CIT was administered. This could be explained by the decreased renal conversion of CIT to Arg and/or, a possible saturation of its transporters a certain dose of CIT. Several authors have proposed that CIT uptake uses a different transport system to Arg which is mainly transported through Na+-independent cationic amino acid transporters (CAT-1, 2 and 3) [45]. CIT is transported across the enterocytes to the portal circulation, likely using the Na+-dependent, neutral amino acid, including the ASC or B\({}^{0,+}\)-amino acid transporters located in those cells [13; 45; 46; 47].  
According to the pharmacodynamic CIT parameters, this amino acid is well tolerated and under short-term application, no side effects such as gastrointestinal disorders were observed, even when high doses (i.e., 15 g) were applied. This is a positive feature of CIT, since in previous studies the administration of related amino acids (>9 g/day of Arg for 1 week or >10 g/day of ornithine in a single dose) caused nausea, vomiting or diarrhea [48]. The explanation for this may lie in the rapid saturation of intestinal absorption of ornithine and Arg, with high loads inducing osmotic diarrhea [40]. In contrast to Arg and ornithine, intestinal CIT absorption is not a limiting factor in CIT bioavailability, since CIT is well tolerated and recognized as safe for oral consumption [18; 49]. The highest doses of CIT reported are 0.18 g/kg/day (approximately 12.6 g/day in a person of 70 kg) for 7 days [50] and a single dose of 15 g [40].