Single Dose Pharmacokinetic Comparison of Citrulline Dietary 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. 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 a standard 6 g dose of L-citrulline, or a 6 g or 2 g dose of citrulline HCl. Measurement of 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. Despite lower citrulline maximal plasma concentration (Cmax) and area under the plasma vs time curve (AUC) in subjects receiving 6 g citrulline HCl, the resulting arginine Cmax and AUCs were similar to that observed with 6 g L-citrulline. Subjects receiving the 2 g dose of citrulline HCl had lower Cmax and AUC values compared to 6 g doses, however, the time required to reach peak levels of arginine occurred in half the time required for the L-citrulline group (60 minutes for citrulline HCl vs 120 minutes for L-citrulline). While all supplements resulted in increased urinary excretion of citrulline, the elevations were greatest for L-citrulline (45-fold) compared to the 6g (15-fold, 3x less than L-citrulline) and 2g (7-fold, >6x less than L-citrulline) citrulline HCl formulations. The decreased urinary elimination with citrulline HCl is consistent with the improved citrulline to arginine conversion rate observed with the citrulline HCl formulations, and likely accounts for the increased relative arginine bioavailability of the 6 g citrulline HCl (125%) and 2 g citrulline HCl (226%), compared to L-citrulline. Together these studies indicate that dietary supplementation with 2 g citrulline HCl provided a faster and more efficient method for increasing plasma arginine than the L-citrulline formulation.