Quantitative characterization of L-citrulline as a precursor of L-arginine in rats: pharmacokinetic basis for nitric oxide-mediated effects.

L-Arginine (ARG) is the primary substrate for nitric oxide (NO) synthesis via nitric oxide synthase (NOS), and L-citrulline (CIT) is its endogenous precursor. Although oral CIT has been reported to increase systemic ARG levels, the quantitative basis for its in vivo conversion to ARG and contribution to NO-mediated effects remains unclear. Therefore, this study aimed to quantitatively characterize the pharmacokinetic relationship between ARG and CIT in vivo and to determine whether CIT-derived ARG exposure could explain the pharmacodynamic effects observed after oral supplementation. Sprague-Dawley rats received oral ARG (500 mg/kg, n = 6), CIT (500 mg/kg, n = 6), or an equidose L-alanine control (n = 6) daily for 30 days. After 30 days of supplementation, both ARG and CIT groups exhibited significantly elevated plasma NOx levels, approximately 1.6-fold higher eNOS protein expression in the aortic arch compared with controls (p < 0.05), and reduced blood glucose concentrations. Plasma concentration-time profiles of both analytes following intravenous and oral administration of each compound were simultaneously analyzed within a single population pharmacokinetic model. The model estimated higher oral bioavailability for CIT than for ARG (FCIT, 82.2% vs. FARG, 52.6%). It also indicated that CIT elimination was predominantly mediated by conversion to ARG (Fmet = 0.999), resulting in greater systemic ARG exposure following oral CIT than following direct oral ARG administration. These findings provide a quantitative pharmacokinetic basis for the NO-mediated pharmacodynamic effects observed with both compounds and support the role of CIT as an effective oral precursor of ARG.