Pharmacokinetics, tissue distribution, and safety evaluation of a ligustilide derivative (LIGc)

Abstract Ligustilide (LIG) is the main active ingredient of Angelica sinensis (Oliv.) Diels and has a neuroprotective effect against ischemic stroke. However, owing to its multi-conjugated unstable structure, the compound has poor drug-forming properties. Therefore, we synthesized highly stable colorless needle crystals (known as ligusticum cycloprolactam, LIGc) through the structural modification of LIG. After a stability experiment was conducted at room temperature for four months, no impurity peaks were found by HPLC-DAD analysis, which indicated that LIGc resolved the stability issues of LIG. LIGc was absorbed and eliminated rapidly after intravenous administration (Cmax = 6.42 ± 1.65 mg/L at a dose of 20 mg/kg) and oral administration (Tmax = 0.5 h, Cmax = 9.89 ± 1.62 mg/L at a dose of 90 mg/kg, t1/2z approximately 2.5 h). The absolute oral bioavailability (F) of LIGc was clearly higher than the F of LIG reported in the literature (F, 83.97% versus 2.6%). Linear dose-dependent pharmacokinetics were observed after oral administration, with a higher area under the curve (AUC0-t, 22.31 ± 2.88 mg/L*h) observed at 90 mg/kg than that at 45 mg/kg (AUC0-t, 13.673 ± 0.666 mg/L*h). Tissue distribution results indicated that LIGc easily crossed the blood-brain barrier (BBB) and was distributed widely to the main tissues and organs of rats. We also conducted a preliminary safety assessment of LIGc by means of an acute toxicity test in KM mice. All mice had excellent health status (ig, dosage of 5.0 g/kg), with no histopathological changes observed in the main organs.