Pharmacokinetics of senkyunolides I (15) and G (12) in human subjects who received an intravenous infusion of XueBiJing
The details of human pharmacokinetic study are described in the Supplemental Materials and Methods (Human Pharmacokinetic Study of XueBiJing). Senkyunolide G (12) was not detected in human urine after dosing XueBiJing. The data represent the mean ± S.D. For both phthalides, no significant gender differences in maximum plasma concentration (Cmax), area under concentration–time curve from 0 to infinity (AUC0–∞), apparent volume of distribution at steady state (VSS), or total plasma clearance (CLtot,p) were observed after dose correction for the subjects' body weights (P = 0.13–0.99).
| Pharmacokinetic Parameter | Dosage Regimen 1 (1.25-hour infusion, 100 ml/day) | Dosage Regimen 2 (2.5-hour infusion, 100 ml/day) | Dosage Regimen 3 (1.25-hour infusion, 50 ml/day) | |||
|---|---|---|---|---|---|---|
| Male (n = 6) | Female (n = 6) | Male (n = 6) | Female (n = 6) | Male (n = 6) | Female (n = 6) | |
| Senkyunolide I (15) | ||||||
| Cmax (nM) | 313 ± 57 | 391 ± 63 | 262 ± 31 | 328 ± 31 | 165 ± 23 | 212 ± 32 |
| (At 1.25 h after starting the infusion, but before terminating the infusion) | (At 2.5 h after starting the infusion, but before terminating the infusion) | (At 1.25 h after starting the infusion, but before terminating the infusion) | ||||
| AUC0–∞ (nM·h) | 571 ± 115 | 690 ± 144 | 713 ± 84 | 863 ± 97 | 280 ± 23 | 374 ± 66 |
| t1/2 (h) | 0.87 ± 0.09 | 0.79 ± 0.12 | 0.87 ± 0.25 | 0.98 ± 0.13 | 0.68 ± 0.14 | 0.79 ± 0.11 |
| MRT (h) | 1.73 ± 0.14 | 1.69 ± 0.21 | 2.41 ± 0.25 | 2.65 ± 0.19 | 1.52 ± 0.19 | 1.79 ± 0.23 |
| VSS (l/kg) | 1.28 ± 0.10 | 1.24 ± 0.14 | 1.45 ± 0.15 | 1.59 ± 0.09 | 1.13 ± 0.13 | 1.22 ± 0.23 |
| CLtot,p (l/h per kilogram) | 0.748 ± 0.096 | 0.746 ± 0.130 | 0.610 ± 0.116 | 0.605 ± 0.071 | 0.745 ± 0.064 | 0.683 ± 0.087 |
| CLR (l/h per kilogram) | 0.030 ± 0.002 | 0.039 ± 0.014 | 0.025 ± 0.011 | 0.029 ± 0.007 | 0.021 ± 0.008 | 0.025 ± 0.004 |
| fe-U (%) | 4.13 ± 0.61 | 5.14 ± 1.28 | 4.27 ± 1.91 | 4.76 ± 0.73 | 3.71 ± 1.23 | 4.70 ± 1.16 |
| CLR/(GFR × fu) ratio | 0.51 ± 0.03 | 0.65 ± 0.23 | 0.42 ± 0.17 | 0.49 ± 0.11 | 0.35 ± 0.12 | 0.43 ± 0.06 |
| Senkyunolide G (12) | ||||||
| Cmax (nM) | 424 ± 44 | 498 ± 98 | 379 ± 41 | 437 ± 78 | 238 ± 52 | 302 ± 45 |
| (At 1.25 h after starting the infusion, but before terminating the infusion) | (At 2.5 h after starting the infusion, but before terminating the infusion) | (At 1.25 h after starting the infusion, but before terminating the infusion) | ||||
| AUC0–∞ (nM·h) | 1503 ± 176 | 1799 ± 333 | 1622 ± 229 | 1978 ± 258 | 779 ± 284 | 1105 ± 209 |
| t1/2 (h) | 2.18 ± 0.27 | 2.45 ± 0.42 | 2.31 ± 0.35 | 2.26 ± 0.45 | 1.91 ± 0.41 | 2.20 ± 0.51 |
| MRT (h) | 3.72 ± 0.32 | 4.08 ± 0.56 | 4.52 ± 0.52 | 4.54 ± 0.58 | 3.33 ± 0.52 | 3.79 ± 0.74 |
| VSS (l/kg) | 0.10 ± 0.01 | 0.11 ± 0.01 | 0.12 ± 0.01 | 0.12 ± 0.01 | 0.09 ± 0.01 | 0.08 ± 0.01 |
| CLtot,p (l/h per kilogram) | 0.027 ± 0.002 | 0.028 ± 0.004 | 0.026 ± 0.005 | 0.026 ± 0.004 | 0.028 ± 0.007 | 0.023 ± 0.004 |
CLR, renal clearance; fe-U, fractional urinary excretion; fu, unbound fraction of compound in plasma; GFR, glomerular filtration rate; MRT, mean residence time.