Toxicokinetics Of Andrographolide Sodium Bisulfite In Rats After Single Intravenous Injection

Objective To investigate toxicokinetics characteristics of andrographolide sodium bisulfite in Sprague-Dawley rats by a single dosage. Methods24rats were randomly assigned into four groups, namely,100mg/kg-dose ASB,600mg/kg-dose ASB,1000mg/kg-dose ASB and a control group. The ASB groups were induced with tail intravenous injections of10mL/kg body weight. The control group received an equal volume of0.9%NaCl injection solution. Blood samples for determination of plasma concentration of ASB, creatinine and urea nitrogen were obtained via femoral artery just prior to drug administration and at2,10,20,30,60,120,180,240,300,360,420,480,540and600minutes after administration. ASB were determined by HPLC-UV, and plasma urea nitrogen and urine creatinine were determined using established protocols. Toxicokinetics parameters calculations were carried out using compartmental analysis method. Other9rats were randomly assigned into three experimental groups. They received a single injection of ASB at a dose of100,600or1000mg/kg. Microdialysates from kidney were collected every10minutes for4hours after administration. ASB in dialysates were determined by HPLC-UV, and reverse microdialysis was used for recovery calibration to quantify the true concentration. Toxicokinetics parameters calculations were carried out using compartmental analysis method. Results The linear range was5μg/mL-2000μg/mL and1μg/mL-1000μg/mL for ASB in plasma and dialysate, respectively, and the recovery of assay was103.22%-109.72%. The plasma concentration-time curves of ASB were fitted to one-compartment model. The ti/2were6.53±2.00,10.80±1.22and13.59±3.38min respectively. The CL were0.02±0.00,0.01±0.00and0.01±0.00L/kg/min respectively, t1/2was increased and CL was decreased with increased dosage. ACUo-t were6765.89±1011.19,58970.99±9259.37and114224.00±18612.74μg·min/mL respectively. Co were801.95±332.55,3774.15±282.63and5938.58±590.88μg/mL respectively. The ACUo-t and Co were positively correlated with the dosage. The kidney interstitial fluid concentration-time curves of ASB were fitted to one-compartment model. The Tmax were 1.28±0.17,1.16±0.03and1.12±0.05min respectively and the t1/2Ka were0.22±0.04,0.17±0.01and0.17±0.01min respectively, indicating high dose promoted ASB access to kidney. The t1/2K10were11.55±1.94,17.72±1.35and14.69±1.60min, indicating high dose inhibited elimination of ASB in kidney. The Cmax were598.99±325.89,2785.49±213.36and4955.00±395.00μg/mL respectively. The AUC0-t were10325.41±5209.17,74235.29±2479.60and111077.40±18904.93μg-min/mL respectively. Cmax and AUC0-t were positively correlated with the dosage. Conclusions ASB act as linear dynamics process in rats after single tail intravenous injection. Several toxicokinetics parameters changed with increased dosage.