Pharmacokinetics, Amino Acid Responses, and Short-Term Tolerability of Intravenous and Oral L-Citrulline in Healthy Neonatal Holstein Calves.

Abstract

L-citrulline is a precursor for endogenous arginine synthesis, supporting nitric oxide production and urea cycle function, yet its pharmacokinetics in neonatal calves are unknown. This study characterized and compared the pharmacokinetics of L-citrulline after intravenous (IV) and oral (PO) administration in healthy neonatal Holstein calves and evaluated associated amino acid responses and short-term clinical and laboratory tolerability. Six healthy male calves (2-4 weeks old) received a single 150 mg/kg dose of L-citrulline as extemporaneously prepared 5% (w/v) IV and 10% (w/v) PO formulations in a randomized 2-period crossover design with a 7-day washout. Blood samples were collected pre-dose and up to 48 h post-dose. Plasma amino acids were quantified by LC-MS/MS, and pharmacokinetic parameters were estimated using non-compartmental analysis. After IV administration, the highest observed total plasma L-citrulline concentration was detected at the first post-dose sampling time, 5 min after bolus administration (C_peak 2213 ± 629 μmol/L; range, 1329-2830 μmol/L). After PO administration, C_max was 1107 ± 371 μmol/L (range, 623-1478 μmol/L), with a median T_max of 60 min (range, 45-120 min). Baseline-corrected non-compartmental analysis yielded t_1/2 values of 2.32 ± 0.79 h after IV administration and 2.23 ± 0.60 h after PO administration, with AUC_0-∞ values of 4130 ± 558 and 3444 ± 1067 μmol·h/L, respectively. Absolute oral bioavailability was 0.86 ± 0.32 (range, 0.52-1.28). Both routes increased plasma arginine (max +159% IV; +122% PO) and ornithine (max +132% IV; +149% PO) with no clinically relevant adverse effects or laboratory abnormalities during short-term monitoring of clinical, hematological, biochemical, blood gas/electrolyte, and coagulation variables. These findings support further evaluation of L-citrulline as a nutritional and/or therapeutic supplement in neonatal calves.