The Objective of This Study Was to Compare and Quantify the Bioavailability of Citrulline Byproducts in Blood Samples and in Urine Samples After a Single Dose of the Assigned Dietary Supplement. The Treatment Arms Containing the Following Molecules: Citrulline HCL and L-Citrulline,

A SINGLE CENTER, SINGLE-BLIND STUDY DESIGN IN HEALTHY SUBJECTS TO EVALUATE SEVERAL EFFECTS OF CITRULLINE SUPPLEMENTS

Citrulline dietary supplements are of interest for improving cardiovascular and exercise performance. The health benefits of citrulline are attributable to its ability to increase arginine levels in the body through the intestinal-renal arginine conversion pathway. From a dietary supplementation standpoint, citrulline offers advantages over arginine due to its reduced first-pass metabolism and ready conversion to arginine within the body. While L-citrulline is the most widely used citrulline dietary supplement, additional salt forms such as citrulline maleate and citrulline HCl may provide improvements in the delivery of arginine to the body. The present study compared the single-dose pharmacokinetics of L-citrulline and citrulline HCl formulations in healthy human subjects. A total of 17 subjects were randomly assigned to groups receiving either 6 g of L-citrulline, 6 g of citrulline HCl or 2 g of citrulline HCl. The resulting increases in citrulline and arginine in plasma and urine samples were determined using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM/MS). All citrulline dietary supplements examined produced time-dependent increases in plasma citrulline and arginine. Both maximal plasma concentration (Cmax) and area under the plasma vs time curve (AUC) for citrulline were modestly reduced in the 6 g citrulline HCl treatment group, the resulting arginine Cmax and AUCs were similar for both L-citrulline and citrulline HCl at the 6 g dose. While the 2 g dose of citrulline HCl had reduced Cmax and AUC values compared to 6 g doses, the time to reach peak levels of arginine were significantly shorter. Furthermore, examination of the relative arginine bioavailability achieved with the 6 g and 2 g citrulline HCl compared to the 6 g L-citrulline was approximately 120% and 215%, respectively, consistent with an improved citrulline to arginine conversion efficiency with the citrulline HCl formulations.

Inclusion Criteria:

• healthy and hydrated male or female ages 18-64; agrees to refrain from citrulline-rich foods; able and willing to fast 12 hours prior to baseline visit; willing to have blood and urine collections as dictated in the protocol; females of child bearing age have some type of birth control.

Exclusion Criteria:

• female subject is pregnant; allergies or sensitivities to citrulline products; history of losing consciousness during blood collection;past medical history of iron deficiency; history of or current treatment for hypertension, coronary heart disease; or angina pectoris; known kidney function issues or disorders; being treated with ACE inhibitors; cancer diagnosis within 5 years of visit; history of chronic disease.