Table 3.
Clinical studies reporting the pharmacokinetics of arginine/citrulline
| Study type | Subjects | Dosage | PK outcome |
|---|---|---|---|
| Randomized placebo-controlled study [14] | 19 subjects with precapillary pulmonary hypertension | Oral 50 mg/kg L-arginine | - Plasma L-arginine: from 90±4 (baseline) to 274±34 (statistically significant change from baseline) |
| Phase 1 dose escalation [19] | 5 infants and children undergoing cardiac surgery for congenital problems | Stepwise dose escalation: 50 mg/kg, 100 mg/kg and 150 mg/kg; two doses were administered-- one before the surgery and one immediate after the surgery. | - Citrulline plasma clearance, distribution-volume and half-life was 0.6 Lhr−1kg−1, 0.9 Lkg−1 and 1 hour, respectively |
| Controlled study on subjects with MELAS syndrome [23] | 20 subjects (10 with MELAS syndrome and 10 healthy subjects) | L-arginine or L-citrulline: 10 g per m2 body surface area per day for two days. | - Arginine supplementation: plasma arginine increased from 57.1±3.2 (baseline) to. 143.8±9.9 (statistically significant change from baseline) - Citrulline supplementation: plasma arginine increased from 57.6±2.1 (baseline) to. 182±14.4 (statistically significant change from baseline) |
| Controlled crossover study [24] | Five pediatric patients with MELAS syndrome and five healthy children as control | Citrulline/Arginine dose: Patients weighing < 20 kg: 500 mg/kg/dose given orally every 4 hours for 48 hours. Patients weighing ≥ 20 kg: 10 g/m2/day. |
- Citrulline supplementation increased plasma arginine concentration from 64±5.7 to 257±21 μmol/L; - Arginine supplementation increased plasma arginine concentration from 59±5 to 184±14 μmol/L |
| Pilot study in patients with pulmonary hypertension [79] | 10 subjects with pulmonary hypertension | 500 mg/kg of l-arginine as 30-minute infusion | Plasma arginine increased from 59±6 μmol/L to 10,726±868 μmol/L (statistically significant change) |
| Pilot phase-II clinical trial [87] | Five sickle cell disease patients (ages 10-18) | 0.09 to 0.13 g/kg twice daily for four weeks | - Increase of 65% (from 77±9.1 to 127±18) in plasma Arginine |
| Randomized controlled trial of oral citrulline [88] | 40 children undergoing cardiopulmonary bypass | 5 doses (1.9 g per m2 body surface area) | - Plasma L-arginine in citrulline group was significantly higher than placebo group (36 μmol /L vs 26 μmol /L in immediately after operation; 37 μmol /L vs 20 μmol /L at 12 h after operation) |
| A randomized study [98] | Ten healthy volunteers | 0.18 g/kg/d | - Citrulline: increase of 448±92% (from 39±4 to 225±44)- Arginine: increase of 92±57% (from 134±33 to 247 ±62)- Increase in urine and RBC Citrulline- No change in urinary Arginine, nor plasma urea, urinary urea nitrogen excretion thus enhanced nitrogen balance |
| Pharmacokinetic study after watermelon ingestion [99] | Six healthy adults | 3.3 kg wet weight red fruit of ripe watermelon | - Citrulline: increase from 22 μmol/L to 593 μmol/L (range 386 - 1069) 1 h after ingestion - Arginine: increase from 65 μmol/L to 199 μmol/L (range 128 - 251) 2 h after ingestion |
| Pharmacokinetic study after watermelon ingestion [100] | 23 healthy adults | 780 g (i.e., 1 g Citrulline), 1560 g (i.e., 2g Citrulline) watermelon juice for three weeks | - Low ingestion of watermelon juice:12% increase in plasma Arginine - High ingestion of watermelon juice:22% increase in plasma Arginine, 18% increase in plasma Ornithine. |
| Pilot study in patients with pulmonary hypercholesterolemia [101] | 10 subjects | Oral L-arginine (5 or 7 g) followed by intravenous L-arginine (10 or 30 g) after 8 hours at each of the four different visits | - Mean Cmax range after oral dose: 42.8 to 46.5 μg/mL - Mean AUC range after oral dose: 651 to 894 μg.min−1.ml−1.g−1 - Mean AUC range after IV dose: 1762 to 1926 μg.min−1.ml−1.g−1 - Mean non-renal clearance: 564.4 to 586 mL/min - Mean bioavailability: 0.37 to 0.52 |
| Randomized pilot study in patients with moderately severe malaria [103] | 78 subjects; 48 in the observational group and 30 received L-arginine | 3, 6, or 12 g L-arginine infused over 30 minutes | - Follows a two-compartment pharmacokinetic model - Clearance from central compartment: 31 Lhr−1 - Clearance from peripheral compartment: 74 Lhr−1 - Distribution volume (central): 27 L - Distribution volume (peripheral): 21 L |
| Randomized pilot study in patients with severe malaria [104] | 8 subjects: two received saline and 6 received L-arginine | 12 g L-arginine infused over 8 hours | - Follows a two-compartment pharmacokinetic model - Clearance from central compartment: 61.8 Lhr−1 - Clearance from peripheral compartment: 21.4 Lhr−1 - Distribution volume (central): 115 L - Distribution volume (peripheral): 70.9 L |
| Phase 1 dose finding study in patients with sickle cell disease [105] | 8 subjects | Step 1: Bolus L-citrulline 20 mg/kg Step 2: 7 mg/kg per hour continuous infusion of L-citrulline |
- Peak plasma concentration of L-citrulline after bolus dose: 257 μmol/l - Clearance and distribution volume after bolus administration were 0.52±0.13 L.h−1.kg-1 and 0.50±0.14 L.kg-1, respectively - Clearance and distribution volume after continuous infusion were 0.52±0.17 L.h−1.kg-1 and 0.41±0.02 L.kg-1, respectively |
| Single-blind crossover study [97] | 8 healthy adults | 2, 5, 10 or 15g of Citrulline | - After ingestion of 10 g of Citrulline- - Citrulline Tmax = 0.72±0.08 h, Cmax = 2756±70μmol/l - Arginine Tmax = 1.67±0.05h, Cmax = 280 ±1043μmol/l |
| Double-blind randomized placebo-controlled crossover study [96] | 20 healthy volunteers | Citrulline: 0.75, 1.5 and 3g twice daily Arginine: immediate release (IR) 1g tid, sustained release (SR) 1.6 twice daily for 1 week | - After load of 3 g Citrulline- - Citrulline: Tmax = 0.7±0.1 h, Cmax = 846±45μmol/l- - Arginine: Tmax = 1.4±0.1h, Cmax = 149 ±42μmol/l |
| Randomized placebo-controlled trial [88] | 40 children undergoing surgery to correct congenital heart lesions | Citrulline 1.9 g/m2/dose x 5 The total dose of 9.5g /m2 |
12h postoperative: - Citrulline: 37 (18-83) vs 20± (15-29) (placebo) - Arginine: 36±24 vs. 23±1357 and 85% increases in mean plasma levels of Arginine and Citrulline, respectively |
‘≥’ = greater than or equal to; ‘<‘ = less than; Arg=arginine; Cmax = maximum plasma concentration; Cit= citrulline; d= day; g= gram; h= hour; kg= kilogram; L= liter; m2= meter squared; mcg= microgram; MELAS= mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; mg=milligram; mmol= millimole; PAH=Pulmonary Arterial Hypertension; tid= three-times daily; vit = vitamin; μmol= micromole; Tmax = time after dose to observe maximum plasma concentration