Comparison of plasma concentrations of the 29 selected endogenous metabolites in cynomolgus monkeys (n = 3) following intravenous administration of PROB alone (40 mg/kg), FSM alone (2 mg/kg), and PROB with FSM
Plasma concentrations of approximately 230 endogenous metabolites were determined by liquid chromatography-mass spectrometry (Supplemental Table 1). Each determination was made in samples collected at 1, 3, and 24 hours postdose from three cynomolgus monkeys, and values for compounds with ≥3.0-fold different plasma concentration at any of three time points in the monkeys treated with PROB and FSM are presented. The P values were determined by paired Student’s t test (Supplemental Table 1).
| Metabolite Type and Name | Ratio of PROB Alone to FSM Alone | Ratio of PROB with FSM to FSM Alone | ||||
|---|---|---|---|---|---|---|
| C1 h | C3 h | C24 h | C1 h | C3 h | C24 h | |
| Dicarboxylic acids and derivatives | ||||||
| C18-di-OH dihydroxyoctadecanoic acid | 5.1 | 7.6 | 2.1 | 11.7 | 9.5 | 2.5 |
| C18-2 dicarboxylic acid | 3.2 | 3.7 | 0.8 | 8.6 | 5.1 | 0.8 |
| C20-4 dicarboxylic acid | 3.0 | 3.6 | 0.7 | 8.8 | 5.5 | 0.5 |
| C18-1 dicarboxylic acid | 2.7 | 3.6 | 0.7 | 7.8 | 5.8 | 0.5 |
| C16-1 dicarboxylic acid | 2.4 | 2.0 | 0.6 | 4.6 | 2.8 | 0.8 |
| TDA | 2.3 | 3.7 | 2.6 | 8.8 | 13.7 | 2.0 |
| C12 dicarboxylic acid | 2.1 | 3.7 | 1.2 | 1.8 | 2.4 | 2.0 |
| C10-1 dicarboxylic acid | 2.1 | 2.8 | 0.7 | 3.4 | 4.5 | 0.7 |
| C12-1 dicarboxylic acid | 2.1 | 1.2 | 0.9 | 3.1 | 1.7 | 0.8 |
| C12-OH hydroxydidecanoic acid | 2.0 | 1.3 | 1.3 | 3.5 | 2.6 | 1.4 |
| C14-1 dicarboxylic acid | 1.9 | 2.3 | 1.6 | 4.2 | 4.4 | 1.7 |
| Unsaturated tetradecanoyl carnitine (C14-1) | 3.9 | 1.0 | 0.5 | 2.8 | 1.5 | 0.5 |
| Unsaturated lauryl carnitine (C12-1) | 3.3 | 1.1 | 0.6 | 1.9 | 1.2 | 0.6 |
| Lauryl carnitine (C12) | 3.0 | 1.1 | 0.5 | 1.7 | 0.9 | 0.5 |
| Small acids produced by gut microflora | ||||||
| Indole-3 acetic acid | 8.6 | 11.2 | 1.6 | 7.6 | 7.7 | 1.7 |
| Cresol sulfate | 3.9 | 5.6 | 2.3 | 4.9 | 7.1 | 2.6 |
| Phenyl sulfate | 3.1 | 2.9 | 1.5 | 2.6 | 3.4 | 1.6 |
| Phenyllactic acid | 2.9 | 3.3 | 2.2 | 3.3 | 3.0 | 2.0 |
| Indoxyl sulfate | 2.8 | 2.8 | 1.0 | 6.4 | 7.5 | 1.2 |
| Phenylacetylglycine | 2.6 | 3.3 | 0.5 | 3.4 | 3.4 | 0.6 |
| Amino acids and derivatives | ||||||
| Hydroxy-isovaleric acid | 3.9 | 1.5 | 4.4 | 12.6 | 1.8 | 6.2 |
| Tyrosine | 3.1 | 2.6 | 1.5 | 2.5 | 1.6 | 0.4 |
| Aspartic acid | 2.2 | 3.0 | 2.2 | 1.6 | 2.5 | 0.5 |
| Others | ||||||
| PDA | 4.5 | 4.8 | 1.4 | 5.6 | 6.0 | 1.5 |
| HVA | 4.1 | 3.2 | 0.8 | 4.6 | 4.0 | 1.3 |
| Glucuronic acid | 8.8 | 8.5 | 2.6 | 10.5 | 11.2 | 2.4 |
| Pantothenic acid | 2.8 | 1.1 | 0.8 | 3.0 | 1.7 | 0.9 |
| Xanthurenic acid | 3.8 | 5.2 | 0.4 | 7.4 | 8.1 | 0.7 |
| Kynurenic acid | 3.5 | 4.1 | 0.6 | 6.6 | 6.0 | 1.0 |