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.